NL8200549A - PYRIDO 1,4BENZODIAZEPINES SUBSTITUTED BY A PHENYL GROUP AND INTERMEDIATES THEREFOR. - Google Patents

Description

% VO 2539

Phenyl-substituted pyrido [1,1 +] benzodiazepines and intermediates therefor.

The invention relates to novel pyrido [1, i +] ben-zodiazepines, to pharmaceutical preparations containing them and to methods of treating depression in humans.

British Patent 907.6-6 describes the preparation of dibenzodiazepines, which are substituted on carbon by phenyl groups and on the bridge nitrogen between the phenyl rings by an alkyl or aminoalkyl group.

Greig, M.E. et al. in J. Med. Chem. 14. No. 2, biz. 153 (1971) describes dibenzodiazepines analogous to those just mentioned which are useful against anaphylactic shocks,

Japanese Patent 73 / ^ 3,520 (CA 8θ, 133501η describes 6-phenyl-2,3, ^, ^ -a-tetrahydro-1H-pyrido [2,3-b] [1, U] benzodiazepines with antispasmodic action which are prepared, for example, from 2-aminobenzophenones and ornithine.

The novel pyrido [1, dibenzodiazepines, according to the invention have the general formula 1 of the formula sheet wherein N inside the ring indicates that one of the ring atoms is a nitrogen atom, while 112 1 R is a hydrogen atom, a lower alkyl group, -alk - Nr R or -alk -N = CH-OC H; i ^ 2 20 R and R each a hydrogen atom, a lower alkyl group, an -0 (0) -0- lower 12. alkyl, or R and R together with the adjacent nitrogen atom may form a heterocyclic group selected from 1-phthalimido, 1-pyrrolidinyl, k-morpholino, 1-piperazino and 1-substituted piperazin-1-yl groups, 25 -An is selected from 2-, 3- and h-pyrridinyl, 2- or 3-thienyl or phenyl groups, where the phenyl group may be substituted by one to 3 groups selected from halogen atoms, lower alkyl groups, lower alkoxy groups, trifluoromethyl or nitro groups,

Any straight or branched chain hydrocarbon group having 1 to 8 carbon atoms, 30 Z is selected from hydrogen or halogen atoms, lower alkyl groups, lower alkoxy groups, hydroxy groups or nitro groups, I is selected from the group consisting of hydrogen atoms or one or two groups selected from lower alkyl groups lower alkoxy groups or hydroxy-8200549 * S '2 groups can be the same or different, n is equal to 0 or 1, t file, from n = 0, the dotted line is a single bond, or the acid addition salts thereof.

The compounds of formula 1 have value for the treatment of depression or as intermediates in the preparation of other compounds of formula 1.

The new [2- [(amino-pyrridinyl) amino] phenyl] arylmethanone intermediates (or precursors) which form in the reaction mixture before they are cyclized into diazepines and are additionally useful as depressants, are represented by formula 2 of the formula sheet, wherein the various substituents have the above meanings and their pharmaceutically acceptable acid addition salt.

15 In further defining the symbols in the formulas of the formula sheet and sailing that appear elsewhere in this description and claims, the terms below have the following meanings:

The group "alk" a straight or branched chain hydrocarbon chain having 1 to 8 carbon atoms is illustrated by a methylene, ethylene, propylene, ethylidene, 1,2-propylene, isopropylidene, or 1,3-butylene group and the like.

By "low alkyl" are meant straight or branched chain hydrocarbon groups having up to 8 carbon atoms and are illustrated by groups such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert .butyl, amyl, isoamyl, hexyl, heptyl, octyl groups and the like.

By "halogen" are meant chlorine, bromine, fluorine and iodine and preferably chlorine, bromine and fluorine.

By "U-substituted piperazin-1-yl" is meant a piperazine substituted in the U-position by a blocking lower alkyl group or a lower alkyl carbonyl group, which may be removed at a later stage to form the unsubstituted piperazine.

Pharmaceutically acceptable acid addition salts are the salts formed by the pyridobenzodiazepines of the invention with a skin random acid, which is physiologically acceptable for beak blood 8200549 * 3 animals, which may be skin salts formed by strong or weak acids. Examples of strong acids are hydrochloric, sulfuric and phosphoric acids. Examples of such acids are fumaric, maleic, succinic, oxalic, cyclohexanoic and the like.

The 6-aryl-11H-pyrido [2,3-b] [1-benzodiazepines and the 5,6-dihydro derivatives many of which fall under formula 1 have the formula 1v of the formula sheet.

The 6-aryl-11H-pyrido [3] ^] [1] benzodiazepines and their 5,6-dihydro derivatives of formula 1 are of the general formula 1x.

The 10-aryl-5H-pyrido [U, 3-b] [1, U] -benzodiazepines and their 10,11-dihydro derivatives many of which fall under formula 1 have the general formula 1y of the formula sheet.

The 1Q-aryl-5H-pyrido [3,2-b] [1, k] benzodiazepines and their 10.11-dihydro derivatives many are included in formula 1 of the formula 1z of the formula sheet.

In all formulas Iv to Iz, the symbols R, Ar, Z and Y have the above meanings.

CM to investigate the depression against the compounds of the invention according to the method used by Englehardt, E.L. et al., J. Med. Chem. 11 (2): 325 (1968) previously has been used to demonstrate the variety of compounds. The tests were conducted as follows: 20 mg / kg of the test compound is administered intraperitoneally to 5 adult mice (ICR-DUB strain) approximately 30 minutes before administration of a ptotic dose (32 mg / kg IP ) tetrabenazine (as the methane sulfonate salt). 30 minutes later, the presence or absence of complete eyelid closure (ptosis) in each animal was determined. For each compound tested, an ED <-q (Median's effective dose) for 3Q blocking the tetrabenazine induced depression in mice can be determined by the procedure described by Litchfield et al., J. Pharmacol. Exp. Therap. 96: 99-113 (19 ^ 9)

Compounds of the invention covered by formula 1, which are frequently anti-depressant in the above-mentioned procedure, have formula 1p of the formula sheet, comprising: 1 1 2 R a hydrogen atom, a lower alkyl group or a group -alk -R-R R; 1 2.

R and R each have a hydrogen atom or a lower alkyl group or together with the 8200549 «Ί? k adjacent nitrogen atom represent a heterocyelic group selected from 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl or 4-lower alkyl-piperaz in-1-yl;

Ar is selected from the group consisting of 2,3- or 4-pyridinyl, 2- or 3-5 thienyl and phenyl groups, the phenyl group may be substituted by one or three equal or different groups selected from halogen atoms, lower alkyl groups , lower alkoxy groups, trifluoromethyl groups or nitro groups.

A I represent a straight or branched chain hydrocarbon having 1 to 8 carbon atoms, 10 Z a hydrogen or halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group or a nitro group, Y represents a hydrogen atom or 1 or 2 equal or different lower alkyl groups, lower alkoxy, or hydroxy groups, m equals 0 or 1 and when m equals 0, the dot-15 line represents a double bond, and their pharmaceutically acceptable acid addition salts.

. . . 1

The compounds of formula 1p where R is an -alk - and 12 1 2 R and R group and R and R represent a lower alkyl group or a hydrogen atom have been found to give rise to little occurrence of antihistamine, anticholinergic and cardiotoxic side effects, research in animals.

The pyridobenzodiazepines, which are valuable in the treatment of depression, are the following:

Example 25 No. Active substance (free base) 9 N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1, U] benzodiazepine-11-propanamine 23 6- (fluorophenyl) -N, N dimethyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine 6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11- propanamine 28 K-methyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine 52b 6- (2-chlorophenyl) -N, N-dimethyl-11 H-pyrido [2,3-b] [1, ^] benzodiazepine-11-propanamine · Some compounds of formula 1, wherein the R moiety contains a phthalimido, chlorine, carbamoyl or imidate component, occur more suitable as intermediates than for treatment of pressures.

Therefore, an object of the invention is to freshly chafffer 6-aryl-11H-pyrido [1, k] pyridobenzodiazepines, with anti-depression efficacy.

Another object is to provide a method of treating depression and pharmaceutical preparations for use therewith.

Another object is to provide new intermediates for the redirection of aryl group-substituted 11H-pyrido [1,1] benzodiazepines, which are antidepressant, while some of these intermediates themselves are also antidepressant.

Other objects and advantages of the invention will be apparent to those skilled in the art, and others will be apparent from the description below of the preferred embodiments of the invention and from the claims.

The invention encompasses the novel pyridobenzodiazepines and the intermediates used in methanol, many of which have been mentioned above in formulas 1 and 2 as new compounds and the use of these compounds against depression or as intermediates in the preparation of other depression control agents.

The reaction sequence for the preparation of the compounds of the invention is indicated in the reaction equations in Scheme A. Other procedures for preparing some compounds of Formula 1 are indicated by the reaction equations in Schemes b, c and d.

25 Methanones of Formula 2 (Scheme A).

The methanone intermediates are prepared by heating a mixture of the haloamino pyridine with an aminobenzophenone for a shorter time than necessary for cyclization to the pyrido benzoaiazepine as can be seen from mass spectrographic chemical analysis under ionization.

For the [2 - [(3-amino-2-pyridinyl) amino-phenylmethanones, the required conditions are about 1-1.5 hours at 170-200 ° C. These methanones can also be isolated as main product by cooling and adding a suitable organic solvent, for example methylene chloride, which dissolves the unreacted starting materials and some cyclized compound (1a), followed by conventional isolation methods, such as partitioning between the solvent and a base dissolved in water or water / methanol, followed by washing, drying, evaporating to dryness and crystallizing from a suitable solvent.

Unsubstituted pyridobenzodiazenines of formulas 1a and 1a-1 (RH), (scheme A) 5 The purified or impure compounds of formula 2 can then be further heated in an aprotic solvent, to cyclize them to compounds of formula 1a, while leaving the reaction mixture water is removed in the usual manner, for example under reflux, using a water trap. However, it is not necessary to interrupt heating at the intermediate stage. Usually, it is sufficient to continue heating the original reaction mixture, i.e., the compounds of formulas 3 and U, for a longer period of time so that the cyclization to form the compound of formula 1a occurs. Regardless of which of these methods is used for cyclization, the relationship between reaction time and temperature will vary slightly depending on the starting materials used, but it is only necessary to heat sufficiently long to obtain the desired product as shown by chemical ionization mass spectrography. The unsubstituted pyrido-benzodiazepine-20s are purified by dividing them between a suitable solvent, such as methylene chloride and a solution of an aqueous base, washing and drying the organic layer, and then evaporating the solvent and chromatographing the residue with a suitable solvent mixture, for example acetone / benzene. The corresponding dihydrodiaze-. Pine can be prepared by reduction with sodium boron cyanohydride.

Substituted pyrido-benzodiazepines of formulas 1b and 1b (R = lower alkyl), (scheme A)

Compounds of formula 1a (or 1a-1), in which R is a hydrogen atom, are alkylated or introduced groups, which will lead to alkylamines by reacting them first with sodium hydriae and then with a suitable reagent, which is represented 1 by haloalkalk Q where "alk-" has the above meanings and Q is defined in Scheme A. The compounds suspended in a suitable solvent, for example dimethylformamide, are added to a stirred suspension of sodium hydride in the same solvent.

The halo-alk1-Q reagent (alkylating agent or an agent 8200549 4 »

T

to alkylation) is added at about room temperature and the reaction mixture is stirred until the conversion is complete, as can be seen, for example, by thin layer chromatography. The unreacted sodium hydride is decomposed by adding the mixture to water, after which the product is extracted with a suitable solvent, such as methylene chloride, followed by extraction of the solvent layer with acidified water, after which the product is isolated from the water layer by neutralization. grating and re-extracting with methylene chloride followed by evaporation and precipitation, preferably as an acid addition salt, eg the fumarate, hydrochloride, oxalate, maleate and the like. Once an acid addition salt has been obtained and purified, the free base can usually be reformed therefrom by dividing the salt between an aqueous solution of base and a suitable solvent such as methylene chloride and then evaporating the methylene chloride layer to dryness.

The corresponding dihydrodiazepines can be prepared by reduction with sodium boron cyanohydride. It is also possible to convert the compounds of formula Ib, in which Q is a halogen atom, into compounds, in which Q is -11- (lower alkyl) 2, by reaction with an appropriate dialkylamine, as indicated in the reaction scheme B.

The primary amines of formula 1c, ie R and R are both a hydrogen atom, are prepared from the -alk - tc - (1-phthalimido) derivatives, as shown in scheme A, by reaction with hydrazine hydrate according to the method described in Org. Syn. Coll. Full.

Ill, biz. 151 - 153. Usually, refluxing for 2-3 hours is sufficient, after which aqueous acid is added and the mixture is filtered. The primary alkyl amines are isolated from suitable solvents such as isopropanol. In isolation, the hydrochlorides and the hydrochloride hydrates are the preferred salts. The corresponding dihydrodiazepines can be obtained by reduction with sodium boron cyanohydride.

The alk - u - monoalkylamines of the formula 1e, in which 1 2,.

R is a methyl group and R is a hydrogen atom can be prepared as indicated in scheme A by boiling the primary HHg derivatives of formula 1c or 1c-1 with triethyl orthoformate for sufficient time to prepare the 35 methanimide acid esters of formula 1-d which is then reacted with sodium borohydride. The unreacted borohydride is decomposed with water and the product is extracted with a concentrated solvent such as ethyl acetate and can be purified by column chromatography and partitioned with a base. solvent. The hydrochlorides are preferably used as salts in this isolation step. This method is further illustrated in Examples 27 and 28. The corresponding dihydrobenzodiazepines can then be prepared by reduction with sodium boron cyanohydride.

T

-Aik - ib monomethylamines can also be prepared by reacting the etbyl chloroformate primary amine as in Example 27 followed by reduction with lithium aluminum hydride, as indicated in Scheme C.

Another more general alternative for entering the -alk ”” - u) -mono (lower alkyl;) amine groups proceeds through the group: 0 1 ”15 -alk -N-C-0- (lower alkyl), see scheme A.

(lower alkyl) A1 the formulas 1a, 1a-1, 1b, 1b-1, 1b-2, 1b-3s 1b-U, 1c, 1c-1, 1c-2, 1d, 1e, 1e-1 are included by formula 1.

1 2

Compounds of formula 1 in which the group -NR R consists of an unsubstituted 1-piperazinyl group are obtained 1 2 by hydrolysing a compound of formula 1, wherein -NR R is a piperazino group which is in the U-position substituted by an alkylcarbonyl group such as a tert-butoxycarbonyl group.

The preparation of the new [(aminopyridinyl) aminophenyl-aryl] methanones, which are intermediates in the preparation of phenyl-substituted pyrido [1, ii] benzodiazepines, are further illustrated in the following preparations of intermediates 1 - 16. The structures of the intermediates are illustrated in table A.

Preparation of the intermediate methanones Preparation 1 [2 - [(3-Amino-2-pyridinyl) amino] phenyl] phenylmethanone

A stirred mixture of 39Λ g (0.20 mol) 2-amino-benzo-8200549 st-, 9 phenon and 28.3 g (0.22 mol) 3 ”amino-2-chloropyridine was heated at 180 ° C in a nitrogen atmosphere for 1 1/2 hours. The mixture was allowed to cool slightly and added slowly. 200 ml of methylene chloride. After stirring for 3 hours and standing overnight at room temperature, 20.1 g of solid was filtered off and recrystallized twice from a mixture of methanol and isopropyl ether to obtain 0.3 g of solid, presumably the hydrochloride, mp 187-190 ° C. This solid was dissolved in a mixture of water and methanol, made basic with 3H HaOH and extracted with methylene chloride. The combined methylene-10 chloride extracts were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from isopropyl ether (activated carbon) to yield 2.1 g of product mp 91 - 93 ° C. For analysis, it was dried overnight at room temperature and 0.02 mm of mercury pressure. Analysis calculated C 7 ^, 72, H 5.23, N 1 ^, 52 15 found C 7 ^, 9 ^, H 5.23, H 1 ^, 69

Preparation 2 [2 - [(3-Amino-2-pyridinyl) amino] -U-chlorophenyl] phenylmethanone

A stirred mixture of 23.2 g (0.1 mole) 2-amino-U'-chlorobenzophenone and 1.2 g (0.11 mole) 3-amino-2-chloropyridine was heated at 180 for 2.5 hours ° C under a nitrogen atmosphere. After cooling to room temperature, the mixture solidified and was broken with a spatula. The solid was suspended in 100 ml of methylene chloride and filtered. The filter cake was dissolved in a mixture of water and methanol, made basic with 3H HaOH solution and extracted twice with methylene chloride. The combined methylene chloride extracts were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crystallized residue was triturated in isopropyl ether and the 16.7 g of solid was filtered off. A 3 g sample was recrystallized from isopropyl ether to yield 1.6 g of product with a melting point of 15-155 ° C.

Analysis: Calculated C ^ H ^ CIHO ^: C 66.77, H U, 36, H 12.98 Found: C 67.06, H ^, 36, H 13.17

Preparation 3 [2-f (3-Amino-2- (pyridinyl) amino) phenyl] (with hylphenyl) -methanone 35 A stirred mixture of 20.0 g (0.095 mol) 2-amino-1 + r- methyl benzophenone and 13.95 g (0.10¾ mol) 3-amino-2-chloropyridine (96 $) 8200549 10 was heated at 180 ° C for 2 hours in a nitrogen atmosphere. The mixture solidified on cooling to a glassy solid, which was crumbled, triturated in methylene chloride and stirred overnight. The solid was filtered off and dissolved in warm methanol. This solution was made basic with 3N NaOH solution, diluted with 500 ml of water and extracted three times with 250 ml of methylene chloride. The combined methylene chloride extracts were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The residue, which crystallized on standing, was recrystallized twice from benzene / isooctane to yield 4.2 g of product 10, mp 126-127.5 ° C.

Analysis: calculated C ^ H ^ O: C 75.23, H 5.65, IT 13.85 found: C 75.81, H 5.69, N 13.96

Preparation k [2 - [(3-Amino-2-pyridinyl) amino] -5-chlorophenyl] - (2-chlorophenyl) methanone 15 A stirred mixture of 20.0 g (0.156 mol) 3-amino-2-chloropyridine and 37.3 g (0.14 mol) 2-amino-2 ', 5-dichlorobenzophenone was heated at 190 ° C in a nitrogen atmosphere for 5.5 hours. Thin layer chromatography (5% methanol / benzene on silica gel) indicated that virtually no reaction had occurred. The mixture was stirred at 190 ° C overnight, cooled slightly and 100 ml of methylene chloride was added carefully. The suspension was stirred for 2 hours and the black matter formed was filtered off. The solid was suspended in 500 ml of methylene chloride and 300 ml of dilute NaOH was added. An emulsion was formed and the mixture was filtered, allowing layer separation. The methylene chloride layer was washed with 2 250 ml portions of water by extraction, dried with magnesium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in benzene and filtered through a column of 300 g of Florisil to remove small material.

All fractions were combined and evaporated to dryness under reduced pressure.

Thin layer chromatography showed the presence of two major components with the smallest spot considered. The residue was dissolved in benzene and chromatographed on a 600 g column of Florisil packed in benzene. The largest material was eluted with% acetone / benzene. After evaporation to dryness, the residue was triturated in benzene and recrystallized from benzene / isooctane to obtain 2.7 g of product mp 162-161 ° C.

82 0 G 5 4 9 9 * 11

Analysis: Calcd C 1 H H Cl Cl O: C 60.35, E 3.66, N 11.73. : C 60.67, H 3.67, ST 11.77 *

Preparations 5a to 5h

Following the same procedures as in Preparation 3 and 5 with equal molar amounts of the following substances instead of 2-amino-U '-methylbenzophenone: 2-amino-1 +' -ethylbenzophenone, 2-amino-U'-isopropylbenzophenone, 2 -amino - ^ '- bromobenzophenone, 2-amino-3'-fluorobenzophenone, 2-amino-U'-ethoxybenzophenone, 2-amino-nitrobenzophenone, 2-amino-T-trifluoromethyl-benzophenone, 2-amino- 3'-methylbenzophenone, 15 2-amino-3'-ethylbenzophenone, 2-amino-31-methoxybenzophenone, 2-amino-3 * -ethoxybenzophenone, 2-amino-21-nitrobenzophenone, 2-amino-31-trifluoromethylbenzophenone, 20 2 -amino-2'-methylbenzophenone, 2-amino-2'-ethylbenzophenone, 2-amino-2 '-methoxybenzophenone, 2-amino-2T, U'-dichlorobenzophenone, 2-amino-3', 5'-trimethoxybenzophenone, 25 2-amino-2'-fluorobenzophenone, 2-amino-2'-chlorobenzophenone, and 2-amino-2r-bromobenzophenone, one obtains: a) 12 - [(3-amino-2-pyridinyl) amino] phenyl] - ( --ethylphenyl) methanone, 30 b) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (^ - isopropylphenyl) methanone, c) 12 - [(3-amino-2-pyridinyl) ami no 3 phenyl] - (b-hromphenyl) methanone, dJ [2-1 (3-amino-2-pyridinyl) amino] phenyl] - (3-fluorophenyl) methanone, e) [2-1 (3-amino-2 -pyridinyl) amino] phenyl] - (^ - ethoxyphenyl) methanone, f) 12-1 (3-amino-2-pyridinyl] amino] phenyl] - (^ - nitrophenyl) methanone, 35 g) l2 - [(3- amino-2-pyridinyl) amino] phenyl] - (Utluoromethylphenyl) methanone, h.) [2-1 (3-amino-2-pyridinyl) amino] phenyl] - (3-methylphenyl) methanone, 8200549 12 i) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-ethylphenyl) methanone, j) [2- [(3-amino-2-pyridinyl) amino] phenyl] - (3-methoxyphenyl ) methanone, k) [2- [(3-amino-2-pyridinyl) amino] phenyl] - (3-ethoxyphenyl) methanone, 1) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-nitrophenyl) methanone, 5 m) [2 - [(3-amino-2-pyridinyl) amino] phenyl J- (3-trifluoromethylphenyl) methanone, n) [2 - [(3-amino-2-pyridinyl) amino ] phenyl] - (2-methylphenyl) methanone, o) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-ethylphenyl) metiianone, p) [2 - [(3-amino-2 -pyridinyl) amino] phenyl] - (2-methoxyphenyl) methanone, q) [2- [(3-amino-2-pyridinyl) amino] phenyl] - (2, U-dichlorophenyl) methanone, 10 r) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3 Λ, 5-trimethoxyphenyl) methanone, s) [2- [(3-amino) -2-pyridinyl) amino] phenyl] - (2-fluorophenyl) methanone, t) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-chlorophenyl) methanone, and u) [2- [(3-amino-2-pyridinyl) amino] phenyl] - (2-bromophenyl) methanone. Preparations 6a - 60 15 Following the same procedure as in Preparation 2 but with equal molar amounts of the following substances instead of 2-amino-U-chlorobenzophenone: 2-amino-5-chlorobenzophenone, 2-amino-6-chlorobenzophenone, 20 2-amino-U-fluorobenzophenone, 2-amino-U-bromobenzophenone, 2-amino-J-trifluoromethylbenzophenone, 2-amino-1 + -methylbenzophenone, 2-amino-5-methylbenzophenone, 25 2-amino-6-methylbenzophenone, 2-amino-U-ethylbenzophenone, 2-amino-4-methoxybenzophenone, 2-amino-ethoxybenzophenone, 2-amino-4-nitrobenzophenone, 2-amino-5-nitrobenzophenone, 2-amino-3-methylbenzophenone, and 2-amino-3-chlorobenzophenone, there is obtained: a) E2 - (3-amino-2-pyridinyl) amino] -5-chlorophenyl] phenylmethanone, 35 "b) 12- (3-amino-2-pyridinyl) amino] -6-chlorophenyl] phenylmethanone, c} [2 - [(3-amino-2-pyridinyl) amino] -1- fluorophenyl] phenylmethanone, d) £ 2— (3-amino-2-pyridinyl) amino] -H-bromophenyl] phenylmethanone, 8200549 13 e) [2 - [(3-amino-2-pyridinyl) amino] trifluoromethylphenyl] phenylmethanone, f) [2 - [(3-amino-2-p yriainyl) amino] - ^ - methylphenyl] phenylmethanone, g) [2- [(3-amino-2-pyridinyl) amino 1-5-methylphenyl] phenylmethanone, h) [2 - [(3-amino-2-pyridinyl) amino] -6-methylphenyl] phenylmethanone, 5 i) [2 - [(3-amino-2-pyridinyl) amino] - ^ - ethylphenyl] phenylmethanone, j) [2- [(3-amino-2-pyridinyl) amino ] -H-methoxyphenyl] phenylmethanone, k) [2 - [(3-amino-2-pyridinyl) amino] - ^ - ethoxyphenyl] phenylmethanone, l) [2 - [(3-amino-2-pyridinyl) amino] - U-nitrophenyl] phenylmethanone, m) [2 - [(3-amino-2-pyridinyl) amino] -5-nitrophenyl] phenylmethanone, 10 n) [2- [(3-amino-2-pyridinyl) amino] -3- methylphenyl phenylmethanone, and o) [2- [(3-amino-2-pyridinyl) amino] -3-chlorophenyl] phenylmethanone. Preparations 7a-7c

Using the same procedure as in Preparation 1, but with equal molar amounts of the following substances instead of 3-15 amino-2-chloropyridine: U-amino-3-chloropyridine, 3-araino-chloropyridine, and 2- amino-3-chloropyridine, there is obtained: 20 a) [2 - [(^ - amino-3-pyridinyl) amino] phenyl] phenylmethanone, b) [2 - [(3-amino-k-pyridinyl) amino] phenyl] phenylmethanone, and c) [2 - [(2-amino-3-pyridinyl) amino] phenyl] phenylmethanone.

Preparation 8 [2-f (3-Amino-2-pyridinyl) -amino] phenyl] (3-chlorophenyl) with hanone, 25 Sen stirred mixture of 35 g (0.152 mol) 2-01 ^ 0-3 ^ chlorobenzophenone and 23 kg (0.182 mol) 3-amino-2-chloropyridine was heated at 180 ° C for 2 hours. The hot melt was allowed to cool to 110 ° C and 100 ml of hot toluene was added dropwise with vigorous stirring. The mixture was allowed to cool to 30 ° C with stirring after which 50 ml of methylene chloride was added. After stirring for another half hour, the mixture was filtered and the filter cake was suspended in methylene chloride and stirred for half an hour, after which the methylene chloride was filtered off. The filter cake, which contained the product (25, hg), was partially dissolved in hot methanol (total volume 150 ml) and 50% aqueous NaOH solution was added until the mixture was basic. Ice water was added and the solution was extracted with methylene chloride. This methylene chloride- 8200549

1U

extract was washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in isopropanol and boiled with activated charcoal. The mixture was filtered and evaporated to give a first portion of crystals weighing 16 g (33 #). A portion of the crystals were recrystallized from isopropanol to give a brick red solid, melting point 119-120. ° C. Analysis: calculated C 66.77 j Η U, 37, N 12.98, found C 66.78, H U, fc2, "N 12.9".

Preparation 9 10 i 2 - [(3-Amino-2-pyridinyl) -amino-phenyl1 (U-fluorophenyl) methanone

A stirred mixture of 35 g (0.163 mol) 2-amino-4'-fluorobenzophenone and 27 g (0.21 mol) 3-amino-2-chloropyridine was heated at 175-180 ° C for 2.5 hours. The mixture was allowed to cool to 110 ° C after which 200 ml of hot toluene was added. After cooling to 50 ° C, 50 ml of methylene chloride were added. The solvent layer was decanted to leave a black solid mass. it was dissolved in hot methanol. The solution was evaporated to half its volume and left overnight at room temperature. The mixture was filtered and the filter cake was washed twice by slurrying in methylene chloride. The weight of the crude solid was 22.5 g. The solid was dissolved in methanol and made basic with 50% aqueous HaOH solution. The mixture was extracted with methylene chloride and the extract was dried and evaporated to dryness. The residue was crystallized twice from isopropanol, decolorized by re-boiling with activated charcoal and 1¼ g (28/5) solid obtained with a red-orange color, mp 121.5-122.5 ° C.

Analysis, calculated C 70.35s Η 59.5 N 13.67, found C 70.23 H H 59.5 N 13.6¼.

Preparation 10 30 [2 - [(3-Amino-2-nyridinyl) amino 1-phenyl] (2-thienyl) -methanone

In the same manner as in Preparation 9, (2-amino-phenyl) - (2-thienyl) methanone prepared according to the method of Steinkopf & Gunther, Ann. 522, 28-3½ (1936), reacted with 3-amin <5-2-chloropyridine to form the above compound.

. 8200 549 35 15

Preparation 11 [2 - [(3-Amino-2-pyrldinyl) amino] phenyl1 (3-thienyl) methanone

In the same manner as in preparation 9, dilute (2-aminophenyl) - (3-thienyl) methanol with 3-amino-2-chloropyridine to form the above compound.

Preparation 12 [2-Γ (3-Amino-2-pyridinyl) amino] phenyl3 (2-pyridinyl) methanone

The said compound is prepared by reacting (2-aminophenyl) - (2-pyridinyl) methanone, prepared according to Schofield, K.J.

10 Ghem. Soc., 19 ^ 9S 2 ^ -08-12, with 3-amino-2-chloropyridine.

Preparation 13 [2 - [(3-Amino-2-pyridinyl) amino] phenyl] (3-nyridinyl) methanone

The said compound is prepared by reacting 2-amino-chloropyridine with (2-aminophenyl) (3-pyridinyl) methanone, which was prepared as indicated by Abramovitch RA & Tertzakian G. Tetrahedron Letters, 19 & 3, 1511-15 and Abramovitch, RA et al. Can. J. Chem. ^ 3 (^), T25-31 (1965).

Preparation 1 ^ [2 - [(3-Amino-2-pyridinyl) amino] phenyl1 (^ - pyridinyl) methanone 20 This compound was prepared by reacting (2-amino phenyl) - (U-pyridinyl) methanone prepared according to liann, AJ and Schofield K.J. Chem. Soc. 1952, 583-9 with 3-amino-2-chloro-pyridine.

Preparations 15a - 15g

In the same way as in preparation 1, but with an equal molar amount of the following substances instead of 3-amino-2-chloropyridine: 3-amino-2-chloro-methyl-pyridine, 3-amino-2-chloro- 5-methylpyridine, 3-amino-2-chloro-6-methylpyridine, 30 3-amino-2-chloro-5, β-dimethylpyridine, 3-amino-2-chloro-6-methoxypyridine, 3-amino-U-chlorine -2-methylpyridine, and 3-amino-2-chloro-5-methoxypyridine, there are obtained: 35 a) [2- [(3-amino-1-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, b) [2 - [(3-amino-5-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, 8200549 *>> 16 c) [2 - [(3-amino-6-methyl-2-pyridinyl) amino] phenyl ] phenyl methanone, d) [2 - [(3-amino-5,6-dimethyl-2-pyridinyl) amino] phenyl] phenyimethanone, e) [2 - [(3-amino-6-methoxy-2-pyridinyl) ) amino] phenyl] phenyimethanone, f) [2- [(3-amino-2-methyl-pyridinyl) -amino] phenyl] phenyimethanone, and 5 g) [2 - [(3-smino-5-methoxy-2) -pyridinyl) amino] phenyl] phenylmethanone.

Preparations 16a-16f

In the same manner as in preparation 1, but instead of 3-amino-2-chloropyridine and equal molar amount of the following substances: 10 2-amino-3-chloro-5-methylpyridine, 2-amino-3-chloro- U, 6-dimethylpyridine, 2-amino-3-chloro-5-ethylpyridine, k-amino-3-chloro-5-methylpyridine, U-amino-3-chloro-2,6-dimethylpyridine, and 15 iJ-amino- 3-chloro-2-methylpyridine, one obtains: a) [2 - [(2-amino-5-methyl-3-pyridinyl) amino] phenyl] phenyimethanone, b) [2 - [(2-amino-U, 6 -dimethyl-3-pyridinyl) amino] phenyl] phenyimethanone, c) [2 - [(2-amino-5-ethyl-3-pyridinyl) amino] phenyl] phenylmethanone, 20 d) [2- [(ii-amino- 5-methyl-3-pyridinyl) amino] phenyl] phenyimethanone, e) [2 - [(U-amino-6-methyl-3-pyridinyl) amino] phenyl] phenyimethanone, and f) [2 - [(U-amino -2-methyl-3-pyridinyl] amino] phenyl] phenyimethanone.

T A B E L A

25 ° '_

30 H

Preparation __Ar_ Y Z

1 CgH - Η H

2 CgHj-H U-Cl

3 Η H

35k 2-Cl-C8 H5-H5-C1

5 a) 1 ^ -02Η5-06Η1 | - Η H

8200549

IT

(Continuation)

Preparation_ kr _ Σ%

B) U-i-C ^ -CgH ^ - 'H

c) 4-Br-CgHHH

d) 3-F-C6Hk-ΗH

5 e) U-OCgHj-CgH ^ - --- Η H

f) U-KOg-CgH ^ - Η H

g) i | -CF3-C6H ^ - Η H

h) 3-CH 3 -C 6 HU-Η H

i) 3-CgH-CgH 2 - Η H

io j) 3-οοη3-ο6η ^ - H H

k) 3-OC2H5-C6H2-Η H

l) 2-H02 “CgH ^ - Η H

m) 3-CF3-CgH1 | - Η H

a) 2-0 ^ -0 ^ - Η H

O) 2-C2H5-C6HrrH

p) 2-00 ^ -0 ^ - Η H

q) 2, ii-Cl2-C8 H3-Η H

r) 3, 55- (0CH 3) 3 -CgH 2 -H

s) 2-F-Cg H 2 - Η H

20 t) 2-Cl-C8 H 3 H

и) 2-Br-CgH ^ Η H

6 a) CgH5-H 5-C1 b) CgH5-H. 6-C1

c) CgHj.- H U-F

D) CgH5-H k-Br e) · CgH5-H ^ -CF3 f) CgH5-H k-Me gl CgH5-H 5-Me h). CgH5- H 6-CH3 30 i) CgH5- Η k ~ C2E5 j) CgH5-HU — 0CH3 к) CgH ^ - H U-0C2H5 l) CgH5- H U-NO2 m) CgH5-H 5-NO2 35 a) CgH5- H 3-CH3 o) CgHj- H 3-Cl 8200549 18 (Continued)

Preparation_Ar_ Y Z

8 3-Cl-CgH ^ - Η H

9 W-CgH ^ - Η H

10 2-thienyl Η H

5 11 3-thienyl Η H

12 2-pyridinyl Η H

13 3-pyridinyl Η H

U-pyridinyl - Η H

15a CgHj - ^ -CH3 H

15b CgH5-5-CH3 H

15c CgH5 ~ 6-CH3-H -.

15d CgH5-5,6- (01 ^) 2 H

15th C6H5-6-OCH3 H

15g C6H5-5-OCH3 H

15

H

20

7a CgH5- Η H

t6d C ^ Ec-5-CH-, H

6 5 3

e GgH5-6-CH3 H

f CgHj.- "2-CH3 Ξ 25 \ -A *

H

30 7h CgH ^ - Η H

15f C6H5-2-CH3 H

;

H

8200549 19 (Continued)

Preparation_Ar_ Y Z

7c c6H5 'h h

16a C8 H5-5-CH3 H

* c6h5-M (ch3) 2 H

5 c CgH5-5_G2H5 H

The preparation of new phenyl-substituted pyrido [1,1t] benzodxazepine compounds of the invention and the new method are further illustrated by the following examples. The structure of the compounds prepared in the examples is illustrated in Table B. However, the invention is not limited thereto. Example I

6-Phenyl-11H-pyrido [2,3-b] [1,1b] -benzodiazepine

A mixture of 19> 7 g (0.1 mol) 2-aminobenzophenone and 15.0 g (0.12 mol) 3-amino-2-chloropyridine was heated at 190 ° C in a nitrogen atmosphere for 1.75 hours. . The mixture was cooled to room temperature and partitioned between 3 'aqueous NaOH solution and methylene chloride. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure.

The residue, 32.7 g, was dissolved in benzene and chromatographed on a column of Jlorisil, packed in benzene, eluted with benzene, and mixtures of 1 - 2% acetone with benzene. After evaporation to dryness, the solid was crystallized from benzene to obtain 7 S3 of product, m.p. 106-108 ° C.

Analysis calculated for C ^ H., ^: C T9.68 #, H k, & 3%, N 15, ^ 9 # 25 found: C 79.70, HU, 81, 1115, ½.

Example II

9-Chloro-6-phenyl-11 H -pyrido- [2,3-b 1 f 1, H] -benzodiazepine

A mixture of 15.0 g (0.06 ^ 7 mol) 2-amino-5-chloro-benzophenone and 951 g (0.06U mol) 3-amino-2-chloropyridine was added in an oil bath 0.75 heated in a nitrogen atmosphere at 200 ° C for an hour. The mixture was cooled and methylene chloride was added. The mixture was stirred for 1 hour and then left overnight. The brown solid precipitate (8.7 g). was filtered off. The filtrate was evaporated to dryness under reduced pressure. The residue was combined with the brown solid and partitioned between aqueous NaOH solution and methylene chloride, and the crude product was isolated as in Example 1, but used in the crystallized ethanol as solvent. After recrystallization from ethanol and drying overnight at 82 ° C and 0.1 mm culture pressure, 3.0 g of product obtained, m.p. 156.5-158.5 ° C.

Analysis: Calculated for C 14 H 14 gClN 3: C 70.71, H 3.96, N 13.7 ^ 5 Found: C 70.2U, HU, 01, H 13.76.

Example III

9-Chloro-6-phenyl-11H-pyrido [2,3-b] [1,1-benzodiazepine

A suspension of 6.6 g (0.02 mol) [2 - [(3-amino-2-pyridyl) amino] -1-chlorophenyl] - (phenyl) methanone (preparation 2) in 200 ml of toluene 10 at reflux and boiled overnight in a nitrogen atmosphere. The reaction mixture is filtered while hot and the filtrate is again heated to boiling temperature. The precipitate formed when cooling to room temperature, filtered, and recrystallized from benzene and dried at 97 DEG-98 DEG C. and 0.1 mm kvik pressure for one hour and then 3.7 g overnight at room temperature and 0.1 mm Kvik pressure. fabric obtained with melting point 250.5-252 ° C. The elemental analysis for carbon was found to be high and the product was dried again at 139 ° C (xylenes in the drying cartridge) for 8 hours. How high the carbon content remained high, the mass spectrum and the magnetic proton core resonance spectrum in accordance with the fabricated structure.

Analysis: Calculated for: C ^ H ^ CIN ^: C 70.71, H 3.96, N 13.7 ^ Found: C 71 Λ6, H! +, Θ6, Η 13, U6.

Example IV

8-Chloro-6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido [2,3-b 1 [1, kbenzodia-25 zepine

Further eluting the Florisil column in preparation U with 10-15 # acetone in benzene and with 5-25 # methanonin benzene gave the fractions of the compound mentioned in the preamble of this example namely 6, hg and 5.7 g, of which the very impure one. The 30 'fraction of 6.1 kg, which is recrystallized from benzene / isooctane, thereby obtained • 3.7 g of solid obtained with melting point 203 - 206 ° C (decomposition) and which is identified by the chemical ionization mass spectrum, by the and NMR as 8 -chloro-6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido [2,3-b] [1] benzodiazepine.

8200549 21

Example V

6- (1-Chlorophenyl) -11H- pyrido [2., 3-b1 [1, k] benzodiazepine

A mixture of 23.2 g (0.10 mol) 2-amino-V-chlorobenzophenone and 1.7 g (0.11 mol) tri-amino-2-chloropyridine {96%) evaporated 1.5 5 heated at 180 ° C in a nitrogen atmosphere for an hour. The mixture is cooled to room temperature and methylene chloride is added. After stirring for 30 minutes, the solid is filtered and triturated, and hot 190 proof ethanol. The residual undissolved material is filtered off and recrystallized from benzene / isooctane, 2.7 g of which is obtained, with melting point 203-20.5 ° C. For analysis, this was dried overnight at 97-98 ° C and 0.1 mm Kvik pressure.

Analysis, recalculated for C ^ H ^ ClY ^ TO, 71, H 3.96, N 13.7 ^ found: C 70.76, H 3.92, H 13.95

Example VI

6- (1) -Methylphenyl) - 11H-pyrido [2,3-bl [1. Benzodiazepine

A solution of 3.6 g (0.012 mol) [2 - [(3-amino-2-pyridyl) amino] phenyl] (U-methylphenyl) methanone in 100 ml of vessel-free toluene, treated with a catalytic amount of p-toluenesulfonic acid and a refluxed overnight, separated further with a vessel trap. The reaction mixture is filtered while hot. When the filtrate cooled to room temperature, the product precipitated and filtered off. The solidification of the solid after the solvent vas evaporates vas 2.5 g, the melting point vas 203.5 - 205 ° C (decomposition).

Analysis calculated for C ^ H ^ N ^: C 79.98, H 5.30, ΪΓ 1 ^ - .73 25 Found: C 79.95, H 5.27, H 1 ^, 76

Example VII

6- (U-Methoxyphenyl) -11H-pyrido [2,3-b] [1,1U] diazepine

A stirred mixture of 20.0 g (0.088 mole) 2-amino-V-methoxybenzophenone and 13.0 g (0.097 mole) 3-amino-2-chloropyridine (96%) in a nitrogen atmosphere heated for 2.0 hours at 180 ° C. The reaction mixture was cooled to about 70 ° C and 100 ml of methylene chloride was added slowly. After allowing the mixture to cool to room temperature, add another 50 ml of methylene chloride and stir the mixture overnight. The suspended solid is filtered off, air dried, dissolved in methanol and made basic with 3H sodium hydroxide solution. The suspension is diluted with 500 ml of water and extracted with three times 250 ml of methylene chloride. The combined methylene chloride extracts were dried with magnesium sulfate and evaporated to dryness under reduced pressure. Analysis by mass spectrum (E1 and Cl) indicated that the residue was a mixture of [2- [(, 3-amino-2-pyridyl) amino] phenyl] -5 (1-methoxyphenyl) methanone and the title of compound mentioned in this example. The residue was dissolved in 250 ml of toluene with a catalytic amount of p-toluenesulfonic acid and the solution was refluxed overnight in a nitrogen atmosphere while water was separated in a water trap. The reaction mixture was filtered hot. The product precipitated while the filtrate was cooled to. room temperature and it was filtered off. After recrystallization from benzene, the product had a weight of 1.8 g and a melting point of 198.5-200.5 ° C (decomposition).

Analysis: Calculated for C ^ H ^ O: C 75.73, H 5.02, H 13.9¾ 15 Found: C 75.65, H 1.95, H 1U, 03

Example VIII

8-Chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [11-benzodiazepine-11-propanamine oxalate (1: 1)

To a stirred suspension of 1.05 g (0.0 ^ 1 mole) of sodium hydride in mineral oil in 50 ml of anhydrous dimethylformamide under a nitrogen atmosphere was added in portions 6.1 g (0.02 mole) of 8-chloro 6-phenyl-11H-pyrido [2,3-b] [1, h] benzodiazepine. The reaction mixture was stirred at room temperature for 1.5 hours and hydrogen evolution ceased. 3.5 g of 25 (0.022 mol) of 3-dimethylaminopropyl chloride hydrochloride were added portionwise to the mixture. After stirring overnight at room temperature, the reaction mixture was poured into 1600 ml of water and the combination was extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 2 250 ml portions of water, then dried with magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in benzene and chromatographed with acetone / benzene on a 300 g column of Florisil packed in benzene. 1.6 g of the starting material was recovered on eluting with benzene and 3.6 g of material containing the product as the free base was obtained on eluting with acetone / benzene after evaporation of the solvent. A 2.5 g portion of the crude free base was dissolved in hot isopropanol and reacted with 0.8 g (Ο, ΟβΙ mol) oxalic acid dihydrate. The oxalate which precipitated on cooling was filtered off 8200549 23 and recrystallized from ethanol to give 2.2 g of product mp 206-208 ° C. For the analysis, the material was dried in 97 - 98 ° C and 0.02 mm mercury for 5 hours and then at room temperature and 0.02 mm mercury overnight.

5 Analysis: calculated for C ^ H ^ dN ^ O ^: C 62, ^ 3, H 5.2b, N 11.65 found: C 62.52, H 5.23, N 11.76

Example IX

N, N-dimethyl-6-phenyl-11H-ovrido [2,3-b1f1, benzodiazeuine-11-propane-amine fumarate [1:11] To a stirred suspension of 1.68 g (0.070 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide was added portionwise under a nitrogen atmosphere to a suspension of 8.0 g (0.029 mol) of 6-phenyl-11H-pyrido [2,3-b] [1, U] benzodiazepine in 20 ml of anhydrous dimethylformamide. After all was added, the mixture was stirred for 20 minutes, warmed to 65 ° C for 15 minutes and cooled again to room temperature. 5.6 g (0.035 mol) of 3-dimethylaminopropyl chloride hydrochloride were added to the mixture. After stirring overnight at room temperature, thin layer chromatography indicated that the reaction was almost complete. The reaction mixture was poured into 1600 ml of water and extracted with 250 ml of methylene chloride. The methylene chloride extract was washed with 3 350 ml portions of water, dried with. magnesium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride and extracted with 3N hydrochloric acid in 100ml and 150ml aliquots. Unreacted 6-phenyl-11H-pyrido [2,3-b] [1, U] benzo-25 diazepine precipitated from the acidic aqueous solution and separated by carefully pouring the liquid off the solid. The aqueous solution was made basic with 3N sodium hydroxide and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried with magnesium sulfate and evaporated under reduced pressure to give 7.7 g of residue, namely the free base of the compound mentioned in the preamble of this example. A solution of 6.6 g of the residue in hot isopropanol was reacted with 2.15 g of fumaric acid and the mixture was heated until dissolved.

After standing for 8 hours, the precipitated salt was filtered off. After recrystallization from isopropanol / isopropyl ether, 5.9 g of product was obtained, m.p. 171-173 ° C. The drying conditions for the analysis were: 4 hours at 90 ° C and 0.1 mm mercury pressure and then overnight at room temperature 8200549

* V

24 hour Τ3ΐό 0.1 mm mercury pressure.

Analysis C28H28HU0U: c 68.63, H 5.97, IT 11.86 068.37, H 6.05, N 11.73

Example X.

5 IT, H-Dimethyl-6-phenyl-11H-nyrido [2,3-b1 [1,4] benzodiazepin-11-ethanamine fumarate [1; 1]

To a stirred suspension of 1.48 g (0.062 mol) sodium hydride (in mineral oil) and 35 nil anhydrous dimethylformamide was added in portions in a nitrogen atmosphere 7.0 g (0.026 mol) 6-10 phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. After the reaction mixture was cooled to room temperature, 4.46 g (0.031 mol) of 2-dimethylaminoethyl chloride hydrochloride was added in portions and stirring was continued overnight. The reaction mixture was poured into 1500 ml of water and the resulting mixture was extracted with 250 ml of methylene chloride. The methylene chloride extract was washed with three 500 ml portions of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 8.6 g of an oil, the free base corresponding to the compound used in the preamble of this example.

A portion of this oil (6.9 g) was reacted with an equal molar amount of fumaric acid in isopropanol. Addition of iso-propyl ether gave an oily solid. The mixture was evaporated to dryness under reduced pressure and the residue crystallized on standing. The crystals were triturated with acetone and recrystallized from acetone / isopropyl ether to give 4.3 g of the fumara salt with melting point 175-177.5 ° C.

Analysis: calculated for ^ 26 ^ 26¾ ° ¼: C 68.11, H 5.72, N 12.22 found: C 67.88, H 5.72, N 12.17

Example XI

11- [3- (4-morrolinyl) propyl] -6-phenyl-11H-pyrido [2,3-b1 [1,4] benzodiazepine · 30 fumarate [1:11

To a stirred suspension of 1.10 g (0.046 mol) sodium hydride (in mineral oil) in 25 ml anhydrous dimethylformamide under nitrogen pressure was added in portions 5.0 g (0.0184 mol) 6-phenyl-11H-pyrido [ 2,3-b] [1,4] benzodiazepine. The reaction mixture was stirred at room temperature for 15 minutes, heated at 65-70 ° C for 10 minutes and then cooled back to room temperature. U, 1 g (0.02 mol) (3-chloropropyl) morpholine hydrochloride was added to the mixture in portions. The reaction mixture was stirred at room temperature for 16 hours and then poured into 800 ml of water. This mixture was extracted twice with 200 ml portions of methylene chloride. The combined methylene-5 chloride extracts were extracted with two portions of 3N hydrochloric acid, 150ml and 75ml, respectively, and the combined aqueous extracts were made basic with 3N sodium hydroxide solution. The resulting slurry was extracted with two 150 ml portions of methylene chloride and the last two extracts were combined, dried with magnesium sulfate and evaporated to dryness under reduced pressure. The residue, the desired free base, was reacted with an equal molar amount of fumaric acid warm isopropanol and the mixture was treated with isopropyl ether. The fumarate salt was filtered off and recrystallized from ethanol / ethyl acetate to obtain 5.6 g of product mp 15¼ - 157 ° C.

The drying conditions for the analysis were: h hour at 97-98 ° C and 0.1 mm mercury pressure and then overnight at room temperature and 0.1 mm mercury pressure.

Analysis calculated for C ^ H ^ N ^: C 67.69, H 5.88, N 10.88 found: C 67.52, H 5.8 ^, H 10.90

Example XII

H, H-Diethyl-6-phenyl-11H-Oyridof2,3-b] (1,1-benzodiazeoin-11-propanamine oxalate [1: 1]

To a stirred suspension of 1.10 g (0.0 ^ 61 mol) sodium hydride (in mineral oil) in 25 ml anhydrous dimethyl formamide 25 under a nitrogen atmosphere was added in portions 5.0 g (0.018¼ mol) 6 phenyl-11 H -pyrido [2,3-b] [1,1U] benzodiazepine. The reaction mixture was stirred at room temperature for half an hour, heated to 65-70 ° C and slowly cooled to room temperature. To the mixture was added 3.77 g (0.020 mol) of 3-diethyl aminopropyl chloride hydrochloride in portions and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into 750 ml of water and extracted with three times 150 ml of methylene chloride. The combined methylene chloride extracts were extracted with 3 H hydrochloric acid in 150 ml and 75 ml aliquots. The combined aqueous extracts were made basic with 3 H sodium hydroxide solution and then extracted with three 100 ml portions of methylene each. chloride. The combined methylene chloride extracts were dried with 8200549 2β magnesium sulfate and evaporated to dryness under reduced pressure to obtain 7.5 g of the free base of the title compound. A 5.6 g portion thereof is reacted with an equal molar amount of oxalic acid dihydrate in hot isopropanol. The oxalate salt is filtered off, 5.5 g of product are obtained, m.p. 196-199 ° C. The drying conditions for the analysis run: 1 hour at 97 - 98 ° C and at 0.1 mm kvik pressure.

Analysis: Calculated for ^ 7 ^ 0¾0 ^ C 68.3 ^, H 6.37, N 11.81 Found: C 68.31, H 6, ^ 3, N 11.86

Example XIII

9-Chloro-IT, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] ['1 ~ [benzodiazepine-11-pranane amine fumarate [1:11

To a stirred suspension of 0.98 g (0.0 ^ 1 mol) sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide 15 in portions under a nitrogen atmosphere, 5 µg (0.016 mol) of 9-chloro- 6-phenyl-11H-pyrido [2,3-b] [1½] benzodiazepine over k5 minutes. The reaction mixture was stirred at room temperature for 1 hour, warmed to 70 ° C and then slowly cooled to room temperature. To this mixture, dilute in portions and add 3.8U of 20 g (0.018 mol) of 3-dimethylaminopropyl chloride hydrochloride over 30 minutes and stir the reaction mixture at room temperature for 17 hours. The mixture is poured out into 750 ml of water and extracted with methylene chloride in a 150 ml portion and two 100 ml portions. The combined methylene chloride extracts were then fused with 100 ml of water, followed by extraction with 3 H hydrochloric acid in 100 ml and 75 ml portions. The acidic extracts were combined and filtered to remove formed precipitate and the filtrate made basic with 3N sodium hydroxide solution and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were then dried with magnesium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride and filtered through a bed of 50-6 g Florisil in a sintered glass funnel. The bed was successively fitted with mixtures of methanol / methylene chloride with]%, 1%, 3% and 5% methanol, respectively, the filtrates were combined and evaporated to dryness under reduced pressure, the free base of which is used in the preamble of this example. said compound is obtained. This free base was reacted with an equal molar amount of fumaric acid in hot isopropanol to obtain 3.3 g of the fumarate. Melting point 199 - 202 ° C.

Analysis: Calculated for C ^ H ^ li ^ O ^ Cl: C 63.96, H 5.37, N 11.05 Found: C 63.63, H 5.36, N 11.00

Example XIV

6-Phenyl-11 - C 3- (1-piperidinyl) propyl-11H-pyrido [2,3-b] [1, k] benzodiazepine fumarate [1:11

To a stirred suspension of 1.10 g (0.0 ^ 61 mol) sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen was added in portions 5 * 0 g (0.018 mol) 6-phenyl -11H-pyrido [2,3-b] [1,1 +] benzodiazepine. The reaction mixture was stirred for 30 minutes, warmed to 70 ° C and spring cooled to room temperature. To the mixture was added portionwise 1¼ g (0.0203 mol) N- (3-chloropropyl) piperidine hydrochloride and the reaction stirred at room temperature for 16 hours. The mixture was poured into 750 ml water and stirred with 150 ml of methylene chloride for 15 minutes. The water layer was further extracted with another 100 ml of methylene chloride. The combined methylene chloride extracts were extracted with 150 ml and 75 ml of 3N hydrochloric acid and the combined acidic extracts were made basic with 3N IfaOH solution and then extracted with three 100 ml portions of methylene chloride each. The methylene chloride extracts were combined, dried with magnesium sulfate and evaporated to dryness under reduced pressure.

The residue was dissolved in a small amount of methylene chloride and filtered through a bed of 100 g of Florisil in a sintered glass funnel. The bed was successively washed with methylene chloride and with mixtures of methylene chloride with 1%, 2%, 3% and 5% methanol, respectively. All filtrates were combined and evaporated to dryness under reduced pressure. The residue was reacted with 1.3 g of fumaric acid in hot isopropanol and isopropyl ether added. An amorphous precipitate is formed. The entire mixture was evaporated to dryness and the residue was dissolved in 200 ml of ethanol. The solution was heated to reflux, filtered and isopropyl ether was added to the filtrate. After standing overnight, the crystals were filtered off to yield 1.1 g of fumarate, m.p. 153-6 ° C. The drying conditions for the analysis were: k hours at 97 DEG-98 DEG C. and 0.1 mm kvik.

Analysis: Calculated for C ^ H ^ H ^: C 70.29, Ξ 6.29, H 10.93 Found: C 70.38, H 6.32, N 10, £ 2 8200549, i 28

Example XV

6- (4-Chlorophenyl) -H., H-dimethyl-11H-pyrido [2,3-b} [1,4-benzodiazenin-1-propanamine fumarate [1: 1]

To a stirred suspension of 1.57 g (0.065 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide was added 8.0 g (0.026 mol) of 6- (4-chlorophenyl) -11H- in a nitrogen atmosphere pyrido [2,3-bj [1,4] benzodiazepine. The reaction mixture was stirred at room temperature for 1 hour, heated to 80 ° C for 15 minutes and cooled to room temperature. 4.55 g of 10 (0.029 mol) 3-dimethylaminopropyl chloride hydrochloride was added to the mixture in portions and the mixture was stirred at room temperature for one hour. The mixture was poured into 750 ml of water and stirred with 150 ml of methylene chloride for 30 minutes. The water layer was then further extracted with 3 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried with magnesium sulfate and evaporated to dryness under reduced pressure to give the free base of the compound mentioned in the preamble of this example. This free base was reacted with an equal molar amount of fumaric acid in hot isopropanol. After cooling, 3.6 g of the fumarate precipitated (melting point 200.5 - 202.5 ° C). The product was dried in air before analysis.

Analysis: Calculated for C ^ H ^ CIN ^ O ^: C 63.96, H 5.37, N 11.05 Found: C 64.18, H 5.33, N 11.07

Example XVI

8-Chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b1 [1,4] benzodiazepin-11-25 ethanamine oxalate [1:11

To a stirred suspension of 1.05 g (0.044 mol) sodium hydride (in mineral oil) in 25 ml anhydrous dimethylformamide was added in portions 6.1 g (0.02 mol) 8-chloro-6-phenyl-11H- pyri-do [2,3-b] [1,4] benzodiazepine. The reaction mixture was stirred at room temperature for 1.5 hours and hydrogen evolution ceased. The reaction mixture was cooled to 5 ° C and 3.2 g (0.022 mol) of 2-dimethylamino methyl chloride hydrochloride was added in portions and then the mixture was stirred at room temperature for about 60 hours. The reaction mixture was poured into 1600 ml of water and the mixture was extracted three times with 1500 ml portions of methylene chloride. The combined extracts were washed with two 500 ml portions of water, 8200549}.

29 dried with magnesium sulfate and evaporated to dryness under reduced pressure. Thin layer chromatography (20% methanol / benzene on silica gel) indicated that the free base of the compound and starting material mentioned in the preamble of this exemplary title was present. The residue was dissolved in benzene 5 and chromatographed on a column of 200 g Florisil. packed in benzene Starting material 1.3 g of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,1 +] benzodiazepine was eluted with benzene and the free base of the title the above compound was eluted with mixtures of acetone in benzene The free base was reacted with an equal 10 molar amount of oxalic acid dihydrate in boiling isopropanol and the product was recrystallized from isopropanol to give 1.6 g of melting point 228.5 - 232 ° C. The drying conditions for the analysis were 6 hours at 82 ° C and 0.1 mm mercury pressure and then overnight at room temperature.

15 Analysis: calculated for ^ 21 + ^ 23 ^ ¾ ^ 1 C 61.71+, H 1 +, 96, Ν 12.00 found: C 61.62, H 1 +, 95, N 11.98

Figure XVII

8-Chloro-11-methyl-6-phenyl-11E-pyrido [2,3b] [1, k] benzodiazepine

To a stirred suspension of 0.25 g (0.01 mol) of na-20 trium hydride (in mineral oil) in 15 ml of anhydrous dimethylformamide was added in portions 3.05 g (0.01 mol) of 8-chloro-6-phenyl -11H-pyrido [2,3-b] [1,1+] benzodiazepine. The mixture was heated at 60 ° C for about 1 hour, a solution of 1.1 + 2 g (0.01 mol) methyl iodide in 10 ml anhydrous dimethylformamide was dripped over an hour and a half and the reaction mixture was left overnight stirred at room temperature and then poured into 1 + 00 ml water and stirred for an additional 2 hours. The precipitated solid was recrystallized twice from isopropanol to give 2.0 g of product mp 153-156 ° C. Drying conditions for the analysis were 1 hour at 82 ° C and 0.1 mm mercury pressure.

Analysis: Calculated for C ^ H ^ CIH ^: C 71.36, H 1 +, 1 + 1, N 13.11+ Found: 0 71.61+, H 1 +, 1 + 3, H 13.32

Example XVIII

U, N-Dimethyl-6- (1 + -methylphenyl) -11H-pyrido [2,3-b] [1,1 +] benzodiazepine-11-propanamine fumarate (1: 1] 35 To a stirred suspension of 0.51 g (0.022 mol) sodium hydride in 25 ml anhydrous dimethylformamide under nitrogen was added in 8200549 30 portions h, 2 g (0.01 ^ 7 mol) 6- (U-methylphenyl-11H-pyrido [2,3-b] [ 1, 5 benzodiazepine over 1 * 5 minutes. The mixture was stirred at room temperature for 1 hour, heated at 75 - 80 ° C for 1 hour, cooled to room temperature and to a solution of 0.018¼ mol of 3-dimethylaminopropyl chloride. dropwise into 10 ml of anhydrous dimethylformamide The mixture was stirred overnight at room temperature and poured into 1000 ml of water The suspension was extracted with 3 portions of 150 ml of methylene chloride and the combined methylene chloride extracts were extracted with 2 portions of 150 ml of 3H hydrochloric acid A precipitate formed in the acidic solution, which was filtered off and discarded The filtrate was made basic with 311 sodium hydroxide solution and extracted with 3 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried with magnesium sulfate and evaporated to dryness under reduced pressure to leave an oil, namely the free base of the compound mentioned in the preamble of this example. This oil was dissolved in hot isopropanol and reacted with an equal molar amount of fumaric acid. The fumarate crystallized after the solution was cooled to room temperature and it was recrystallized twice from isopropanol / isopropyl ether to obtain 1.7 g of product mp 187-189 ° C (decomposition).

Analysis: C ^ H ^ H ^: C 69.12, H 6.22, N 11.52, C 68.86, H 6.32, N 11.36

Example XIX

6- (U-Methoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1., U] benzodiazepine-11-. Prooanamine fumarate [1: 1T

To a stirred suspension of 0.1 * 5 g (0.0187 mol) sodium hydride in 25 ml of anhydrous dimethylformamide in a nitrogen atmosphere, 1 *, 5 g (0.015 mol) of 6- (U) methoxyphenyl) -11H-pyrido [2,3-b] [1,1 *] benzodiazepine. The mixture was stirred at room temperature for 30 minutes and then heated at 80-90 ° C for 1 hour, cooled to room temperature and then a solution of 0.019 mol 3-dimethylaminopropyl chloride in 5 ml anhydrous dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature overnight and poured into J300 ml water. The suspension was extracted (2 χ) with 150 ml of methylene chloride each time. The combined extracts were washed in 600 ml of water and then extracted with 2 portions of 100 ml of 8200549 31 3N hydrochloric acid each. The solid which precipitated from the combined acidic extracts was filtered and discarded. The filtrate was made basic with 3N sodium hydroxide solution and extracted with 3 portions of 100 ml of methylene chloride. The combined methylene chloride extract was dried with magnesium sulfate and evaporated under reduced pressure. The residual oil was partially crystallized and was triturated with methylene chloride and filtered to leave a 0.32 g residue. The filtrate was evaporated to dryness under reduced pressure and the remaining eight oil was triturated with hot benzene and filtered to leave a 0.8 g residue. The benzene filtrate was evaporated to dryness under reduced pressure and the residual oil was reacted with 1.02 g of fumaric acid in hot isopropanol. After cooling, an oil separated from the solution. The supernatant was poured off and the oil seeded. After partial crystallization, the mixture was filtered to leave 2.5 g of solid, mp 157-160 ° C. An attempt to recrystallize from a mixture of isopropanol and isopropyl ether again yielded a mixture of oil and solid. The mixture was reheated with an additional amount of isopropanol, dissolved, filtered, seeded and cooled. The fumarate precipitated and was filtered to yield 2.0 g of material, mp 159-161 ° C.

Analysis: Calculated for Ο ^ Η ^ Η ^ Ο ^: C 66.92, H 6.02, N 11.15 Found: C 66.90, H 6.08, IT 11.08

Example XX

6- (3-Chloro-phenyl) -11H-pyrido [2,3-b1 [.

A mixture of 1¾ g (0.0 ^ 33 mol) [2 - [(3-amino-2-pyridinyl) amino] phenyl] (3-chlorophenyl) -methanone and 0.3 g p-toluenesulfonic acid in 500 ml Toluene was refluxed overnight with a water trap. After boiling, the portion of the toluene (about 250 ml) was distilled off and the ether solution was filtered. Petroleum ether (30-60 ° C) was added to the cloud point. The solution was cooled overnight, then filtered to yield (after air drying) 10 g (76%) of gold crystals. A portion was recrystallized from isopropanol / isopropyl ether, mp 160-160.5 ° C.

35 Analysis: calculated for Ο ^ Η ^ Ι ^ ΟΙ: C 70.71, H 3.96, N 13.7¾ found: C 70, Vf, H 3.98, N 13.62 8200549 32

Example XXI

6- (3-Chlorophenyl) -ΚΓ, N-dimethyl-11H-pyrido [2,3-t> 1 [1-benzodiazepine-11-propanamine fumarate [1: 1]

To a stirred suspension of 3.0 g (0.07 mol) of sodium hydride (in mineral oil) in 250 ml of anhydrous dimethylformamide was added 8.5 g (0.028 mol) of 6- (3-chlorophenyl) in a nitrogen atmosphere 11H-pyrido [2,3-b] [1] benzodiazepine. The mixture was stirred at room temperature for 30 minutes. The temperature was kept at 80 ° C for 3 hours and then the mixture was allowed to cool to room temperature. A solution of kg g (0.031 mol) 3-dimetbylaminopropyl chloride hydrochloride in 30 ml dimethylformamide was added dropwise to the mixture over 20 minutes. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. Thin layer chromatography indicated that some starting material was still present. An additional amount of sodium hydride, namely 1 g (0.03 mol) was added and then 15 g (0.03 mol) of 3-dimethylaminopropyl chloride hydrochloride was added for 15 minutes and the mixture was stirred for 1/2 hour. Then 20 ml of water was added dropwise and the reaction mixture was filtered and evaporated to dryness on a rotary evaporator. The residue was partitioned between diethyl ether and dilute NaOH solution. The ether layer was washed three times with water and extracted with dilute hydrochloric acid. The water layer was made basic with sodium hydroxide granules and extracted with methylene chloride. The methylene chloride layer was dried and evaporated to dryness leaving 7 5 g of residue. This free base was reacted with fumaric acid and the fumarate was recrystallized from ethyl acetate / ethanol. Melting point 167.5-168.5 ° C.

Analysis: Calculated for C ^ H N ^ Cl: C 63.96 »H 5, ^ 7, N 11.05 Found: C 63.95, H 5.39, N 11.00

Example XXII

6- (U-Fluorophenyl) -11H-pyrido [2,3-b] f1,1] benzodiazepine

A mixture of 11.5 g (0.037 mol) [2 - [(3-amino-2-pyridinyl) amino] phenyl] (4-fluorophenyl) methanone and 0.6 g p-toluenesulfonic acid in toluene was boiled for 2 hours under reflux with a water pan. After boiling, part of the toluene (300 ml) was distilled off and the ether solution was filtered. Petroleum ether (30-600C) was added until the cloud point was reached. The solution was cooled (0 ° C) overnight 8200549/33 and then 10.7 g of crystalline was filtered off. A portion of the material was recrystallized from tilt isopropanol and dried in vacuo overnight at 65 ° C; mp 203-205 ° C.

Analysis: Calculated for C ^ gH ^ K ^ F: C 7 ^, 73, H ^, 18, N 1 ^ +, 52 5 Found: C 7U, 61, H U, 17, N 1 ^, 5 ^

Example XXIII

6 ~ (h-Fluorophenyl) -N, ff-dimethyl-11H-pyridof2,3-b] f 1.Λ benzodiazepine-11-propanamine hydrochloride hemihydrate

To a stirred suspension of 3.6 g (0.075 mol) of na-10 trium hydride (in mineral oil) in 250 ml of anhydrous dimethylformamide was added in a nitrogen atmosphere and in portions 8.7 g (0.03 mol) 6- (4 -fluorophenyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine. The mixture was stirred at room temperature for 30 minutes. The temperature was kept at 80 ° C for 3 * 5 hours and then the mixture was allowed to cool to 55 ° C. A solution of 5 * 2 g (0.033 mol) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide was added dropwise to the reaction mixture.

Stirring overnight at room temperature, thin layer chromatography indicated the presence of some starting material. An additional amount of sodium hydride (3.6 g, 0.075 mol) was added and after stirring for 5 minutes, the reaction mixture was heated at 50-60 ° C for half an hour. In doing so, a green color developed with the formation of gas. The mixture was stirred at room temperature for 3 hours. A solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride in 30 ml of dimethylformamide was added dropwise. (About halfway through this addition, a green color developed and at that time the addition was interrupted for about an hour). The reaction mixture was stirred at room temperature overnight. 30 ml of water was added to the mixture under cooling. After gas evolution had ceased, the mixture was filtered and evaporated to dryness in a rotary evaporator. The residue was partitioned between diethyl ether and water and the ether layer was extracted with dilute hydrochloric acid.

The water layer was filtered an hour and a half later to remove solid. The filtrate was made basic with granules of sodium hydroxide and extracted with methylene chloride. The extract was dried and evaporated to dryness. The residue was divided into 2 equal portions and purified by dry column chromatography on 2 columns (50 x 3.75 cm) of silica gel deactivated by the winding solvent (10% methanol, 1% concentrated ammonium hydroxide, 89 $ methylene chloride). The central portion of the column was cut out and extracted with the developing solvent. The combined extracts were evaporated to dryness under reduced pressure and the residue was dissolved in a mixture of ethyl acetate / ethanol and acidified with concentrated hydrochloric acid. The hydrochloride was recrystallized from a mixture of ethanol and ethyl acetate. The filtered solid was dried at 99 ° G for hours giving the compound mentioned in the preamble as the monohydrochloride hemi-hydrate mp 120-123 ° C.

10 Analysis: Calculated for C ^ gH ^ QHgFgClgO: C 65.7 $, H 6.00, N 13.3 * +

found: C 65.58, H 5.77, R 13M

Example XXIV

11- (3- (1,3-dihydro-1,3-dioxo-2H-1-soindol-2-yl) -propyl] -6-phenyl-11H-pyrido [2,3-b] [1.1-benzodiazepine To a stirred suspension of 0.56 g (0.023 mol) sodium hydride in 25 ml anhydrous dimethylformamide was added in portions 5.0 g (0.018¼ mol) 6-phenyl-1H-pyrido [2,3- b] [1, ^] benzodiaze pine The reaction mixture was heated at 80 + 2 ° C for 1 hour and then cooled to room temperature A solution of 5.55 g (0.020 mol) N- (3-20 bromopropyl) Phthalimide in 10 ml of anhydrous dimethylformamide was added dropwise and after stirring for 16 hours, the reaction mixture was poured into 600 ml of water and stirred for 30 minutes The yellow solid was filtered off and recrystallized three times from isopropanol to obtain 3.7 g of product with melting point 1Uo - 172 ° C.

Analysis: calculated for C 75.97, H ^, 8 ^. N 12.22 found: C 76.25, H U, 87, N 12.3¼

Example XXV

6-Phenyl-11H-pyrido [2,3-b1 (1¼-benzodiazepine-11-propanamine, dihydrochloride, hemihydrate) A mixture of 16.2 g (0.035 mol) 6-phenyl-11- [3- (phthalimido ) propyl] -11H-pyrido [2,3-b] [1] benzodiazepine and 2.29 g (0.0387 mol) hydrazine hydrate (85%) in 175 ml "190 proof" ethanol was boiled for 2 1/2 hours under reflux and then left for 2 hours A solution of 10 ml of concentrated hydrochloric acid in 50 ml of water was added to the mixture The mixture was stirred overnight The solid precipitate was filtered off and discarded. reduced by evaporation to third pressure, the slightly wet residue is suspended in 200 ml of water, the mixture is stirred for 2 hours and then filtered through Celite The filtrate is evaporated to dryness under reduced pressure and the residue is suspended in 100 ml of "200 proof "ethanol and evaporated to dryness under reduced pressure. The last procedure is repeated, The crude moist residue (^ 2.1 g) is recrystallized. from isopropanol stand under 15 hours. After filtration, the solid was dried with 82 ° C over phosphoric anhydride and 0.1 mm Kvik pressure for 3 hours; mp 210-220 ° C (decompn.).

Analysis: Calculated for C 12 H 14 Cl 14 Hg O: C 61 Vf; H 5.65, N 13.65. Found: C 61.36, H 5.72, N 13.90

Example XXVI

6-Phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine

A portion of 6-phenyl-11H-pyrido [2,3-b] [1, U] benzodia-15-zepine-11-propanamine dichloride hemihydrate obtained in Example XXV, diluted in water, basified with dilute sodium. hydroxide and extracted with 3 portions of methylene chloride. The combined methylene chloride extracts were then filtered through a 50-60 g bed of Florisil in a sintered glass funnel. The bed was subsequently washed successively with mixtures of methylene chloride, each containing 1, 2, 3 and 5% methanol, the filtrates were combined and evaporated to dryness under reduced pressure, the free base being formed. Example XXVII

H-f 3-f 6-Phenyl-11H-pyrido [2,3-b] 1-benzodiazepine-11-yl] propyl] methane-25 imidic acid ethyl ester

A solution of 8.8 g (0.021 mol) of 6-phenyl-11H-pyrido [2,3-b] 1-benzodiazepine-11-propanamine in 150 ml of triethyl orthophorate was refluxed for 1/2 hour and then left alone overnight. The mixture is evaporated to dryness in vacuo, the residue is evaporated with petroleum ether (30 - 60 ° C). Chemical ionization mass spectrography indicated that the product was a mixture containing the above-mentioned compound.

Example XXVIII

H-Methyl-6-phenyl-11H-pyrido [2,3-b] [1 Λ] benzodiazepine-11-propanamine, dihydrochloride '

Preparation of the Imidate Ester 8200549 3 6 [Crochet T.A. Method & Blanton C.D. Jr., Synthesis 197 ^ (1) 55-56]

25 g (0.06 mol) of the 6-phenyl-11H-pyrido [2,3-h] [1,1] benzodiazepine-11-propanamine dihydrochloride hemihydrate obtained in Example V were converted into the free base by dividing it between dilute sodium hydroxide and methylene chloride, drying and evaporating the methylene chloride layer, adding dry benzene and evaporating again to remove the benzene. The resulting free base was dissolved in 300 ml (267 g; 1.8 mol) of freshly distilled triethyl orthoformate and refluxed for 9 hours. The mixture was evaporated in vacuo-10, ethanol was added and the mixture was evaporated to dryness again. Conversion of the amidate to amine

The 23 µg (0.061 mol) amidate, obtained as described above, was dissolved in 200 ml of ethanol and sodium borohydrate was added with stirring at 15 - 20 ° C until thin layer chromatography indicated that the reaction was practically complete, as shown by significant amounts of starting material. 50 ml of water was slowly added with stirring and cooling was continued for 15 minutes after the addition of water. The mixture was then drowned in 2 L of water and extracted with ethyl acetate. The ethyl acetate layer was washed with water until neutral washing water was obtained and then saturated with sodium chloride. The resulting ethyl acetate layer was dried and evaporated to dryness. Diethyl ether was added and the mixture was cooled. Some insoluble material was filtered and discarded.

The ether layer was evaporated to dryness and the product was chromatographed on a column of alumina (neutral, activity -1), eluted with ethyl acetate plus methanol, plus traces of triethylamine. The fractions containing a significant amount of product (TLC) were partitioned between ethyl acetate and sodium hydroxide solution. Ethereal HCl solution was added to the ethyl acetate layer and the resulting crystalline product was recrystallized from a mixture of acetonitrile and water. The melting point of the product was 139-111 ° C.

Analysis: Calculated for C22H2 ^ C12: G 63.62, H 5.82, N 13, ^ 9 Found: C 63.81, H 6.15, N 13.60

Example XXIX

H- [3-f 6-phenyl-11H-nyrido [2,3-b1 [1, k] benzodiazepine-11-yl] propyl] carba-xinic acid ethyl ester

To a solution of 1.6 g (0.005 mol) of 6-phenyl-11H-8200549 37 pyrido [2,3-¾1 [1,1 *] benzodiazepine-11-propanamine in dry methylene chloride was added added 0.53 g (0.0052 mol) of triethylamine. 0.5 µg (0.0050 mol) of ethyl chloroformate was added dropwise to this solution with cooling. The mixture was stirred at room temperature for 2 hours. The methylene chloride solution of the product (as indicated by chemical ionization mass spectrography) was washed with dilute NaOH solution saturated with NaCl then dried and evaporated to dryness. The residue was triturated in isopropanol. The yield was 1.5 g.

Example XXX

70 5.6-Dihydro-N.H-dimethyl-6-phenyl-11H-pyrido f 2,3-b] [1,1] benzodiazepine-11-oronanamine, dihydrochloride hemihydrate

A solution of 3.0 g (0.006U mol) of N, U-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine in absolute methanol was adjusted to pH 5, 6 with a solution of HCl in methanol. To this solution was added in a shoot 0.7 g (0.011 mol) of HaBH 2 CH and the reaction mixture was refluxed for 20 minutes.

The methanol was removed in vacuo and the residue was partitioned between dilute HaOH solution and methylene chloride. The methylene chloride layer was dried with magnesium sulfate and evaporated to dryness to leave a residue, which was recrystallized twice from 2-propanol and iso-propyl ether. A yellow solid (1.6 g), 57 $, was obtained which lost its crystal structure on heating. starting at 156-160 ° C with decomposition at 180-195 ° C.

Analysis: Calculated for C ^ gH ^ gHgOCl ^: C 62.73, H 6.6k, H 12.72 Found: C 62.1 * 0, H 6.90, N 12.61

Examples XXXIa - XXXIr

In the same manner as in Example 6, the following methanone compounds were: [2- [(3-amino-2-pyridinyl) amino] phenyl] - (1-ethylphenyl) methanone, [2- [(3-amino) -2-pyridinyl) amino] phenyl] - (1 + -isopropylphenyl) methanone, [2-1 (3-amino-2-pyridinyl) amino] phenyl] - (! * - bromophenyl) methanol, 35 [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-fluorophenyl) methanone, 8200549 38 [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (U-ethoxyphenyl) methanone , [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (U-nitrophenyl) methanone, 5 C 2 - [(3-amino-2-pyridinyl) amino] phenyl] - (U-trifluoromethyl- phenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-methylphenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3 -ethylphenyl) methanone, [2- [(3-amino-2-pyridinyl) amino] phenyl] - (3-methoxyphenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - ( 3-ethoxyphenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-nitrophenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-trifluoromethylphenyl) methanone, [2 - [(3-a mino-2-pyridinyl) amino] phenyl] - (2-methylphenyl) methanone, i 2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-ethylphenyl) methanone, [2 - [( 3-amino-2-pyridinyl) amino] phenyl] - (2-methoxyphenyl} methanone, 25 i 2 - [(3-amino-2-pyridinyl) amino] phenyl] -2, U-dichlorophenyl) methanone, and [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3, H, 5-trimethoxyphenyl) methanone, cyclized to the following pyridobenzodiazepines: 30 a) 6 - (1-ethylphenyl) -1H-pyrido [ 2,3-b] [1, U] benzodiazepine, b) 6- (U-isopropylphenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine, c) 6- (U-bromophenyl) - 11H-pyrido [2,3-b] [1, k] benzodiazepine, d) 6- (^ 4-fluorophenyl) -11 H-pyrido [2,3-b] [1, U] benzodiazepine, e ) 6- (U-ethoxyphenyl} -11 H -pyrido [2,3b] [1,1 *] benzodiazepine, 35 f) 6- (U-nitrophenyl) -11H-pyrido {2,3-b] f1 , 4] benzodiazepine, g) 6 - (^ - trifluoromethylphenyl) -11 H -pyrido [2,3-b] [1, h] benzodiazepine, 8200549 39 h) 6- (3-methylphenyl) -11 H -pyrido [ 2,3-b] [1, U] benzodiazepine, i) 6- (3-ethylphenyl) -11H-pyrido [2,3b j [1, U] benzodiazepine, j) 6- (3-methoxypheny 1) -11H-pyrido [2,3-b] [1,1] benzodiazepine, k) 6- (3-ethoxyphenyl) -11H-pyrido [2,3b] [1,1] benzodiazepine, 5 l) 6- (2-nitrophenyl) -11H-pyrido [2,3-b] [1,1H] benzodiazepine, m) 6- (3-trifluoromethylphenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine, n) 6- (2-methylphenyl) -11H-pyrido [2,3-b] [1,1-benzodiazepine, o) 6- (2-ethylphenyl) -11 H-pyrido [2,3-b] [1, ^ benzodiazepine, p) 6- (2-methoxyphenyl) -1TH-pyrido [2,3-b] [1,1 *] benzodiazepine, 10 µg 6- (2, U-dichlorophenyl) -11H-pyrido [2,3 -b] [1,1] benzodiazepine, and r) 6- (3,5- trimethoxyphenyl) -11 H -pyrido [2,3-b] [1,1benzodiazepine.

Examples XXXIIa - XXXIIo

In the same manner as in Example III, the following methanone compounds are: [2 - [(3-amino-2-pyridinyl) amino] -5-chlorophenyl] (phenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] -6-chlorophenyl] (phenyl) methanone, [2- [(3-amino-2-pyridinyl) amino] -bromophenyl] (phenyl) -methanone, [2 - ((3-amino-2-pyridinyl) amino] -4-fluorophenyl] (phenyl) methanone , [2 - [(3-amino-2-pyridinyl) amino] -U-trifluoromethylphenyl] (phenyl) methanone, [2- [(3-amino-2-pyridinyl) amino] -if — with hylphenyl] (phenyl ) methanone, [2 - [(3-amino-2-pyridinyl) amino] -5-methylphenyl] (phenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] -6-methylphenyl] (phenyl ) 30 methanone, (2 - [(3-amino-2-pyridinyl) amino] -U-ethylphenyl] (phenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] -U-methoxyphenyl] ( phenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] -U-ethoxyphenyl] (phenyl) methanone, [2- [(3-amino-2-pyridinyl) amino] -U-nit rofenyl] (phenyl) 8200549

Methanone, [2- [(3-amino-2-pyridinyl) amino] -5-nitrophenyl] (phenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] -3-methylphenyl] ( phenyl) 5-methanone, and [2 - [(3-amino-2-pyridinyl) amino-3-chlorophenyl] (phenyl) methanone, cyclized to the following benzodiazepines: a) 8-chloro-6-phenyl-11H-pyrido [ 2,3-b] [1, U] benzodiazepine, 10 b) 7-chloro-6-phenyl-11H-pyrido [2,3b] [1, ¾] benzodiazepine, c) 9-bromo-6-phenyl-1 1H-pyrido [2,3-b] [1,1] +] benzodiazepine, d) 9-fluoro-6-phenyl-11H-pyrido [2,3b] [1,1]] benzodiazepine, e) 6-phenyl-9- trifluoromethyl-11H-pyrido [2,3b] [1] benzodiazepine, f) 9-methyl-6-phenyl-11H-pyrido [2,3-b] [1-benzodiazepine, 15 g) 8-methyl-6-phenyl -11H-pyrido [2,3-b] [1,1] benzodiazepine, h) 7-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine, i) 9-ethyl- 6-phenyl-11H-pyrido [2m3-b] [1, U] benzodiazepine, j) 9-methoxy-6-phenyl-11H-pyrido [2,3-b] [1, U] benzodiazepine, k) 9- ethoxy-6-phenyl-11H-pyrido [2,3-b] [1,1-benzodiazepine, 20 1) 9-nitro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine, m) 8-nitro-6-phenyl-11H-pyrido [2,3-b] [1, k] benzodiazepine, n) 10-methyl-6-phenyl-11H-pyrido [2,3b] [1,1] benzodiazepine, and o) 10-chloro-6-phenyl-11H pyrido [2,3-¾] [1,1] benzodiazepine.

Examples XXXIIIa - XXXIIIr In the same manner as in Example XV but with equal molar amounts of the compounds prepared in Example XXXI, the following 6-phenyl-pyrido-benzodiazepines were prepared: a) 6- (U-ethylphenyl) - N, N-dimethyl-11H-pyrido [2,3b] [1,] benzodiazepine-11-propanamine, 30 b) H, N-dimethyl-6- [1 * - (1-methyl-ethyl) phenyl] -11H-pyrido [2,3-b] [1,1 *] benzodia-z-epin-11-propanamine, c) 6- (W-bromophenyl) -H, H-dimethyl-11H-pyrido [2,3-b] [1] benzodiazepine -11-propanamine, d) 6 - (^ - fluorophenyl) -N, H-dimethyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine, e) 6- (Wthoxyf enyl) -H, H-dimethyl-11 H -pyrido [2,3-b] [1,1H] benzodiazepine-11-propanamine, 8200549 41 f) H, H-dimethyl-6-b-nitrophenyl) -11 H pyrido [2,3-b] [1 b benzodiazepine-1-propanamine, g) IT, 1T-dimethyl-6- [k- (trifluoromethyl) phenyl] -11 H-pyrido [2,3-b] [ 1 benzodiazepine-11-propanamine, 5 h) H, N-dimethyl-6- (3-methylphenyl) -11H-pyrido [2,3-b] [1 bibenzodiazepine-11-propanamine, i) 6- (3- ethylphenyl) ~ N, N-dimethy 1-11H-pyrido [2,3-b] [1, b] benzodiaz-epin-11-propanamine, j) 6- (3-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1, ybenzodiazepine-11-propanamine, k) 6- (3-ethoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3b] [1bibenzodiazepine-11-propanamine, 1) N, B-dimethyl-6 - (2-nitrophenyl) -11H-pyrido [2,3-b] [1-benzodiazepine-11-propanamine, 15 m) H, H-dimethyl-6- [h- (trifluoromethyl) phenyl] -11 H-pyrido [2 , 3-b] [1,1] benzodiazepine-1-propanamine, η) N, H-dimethyl-6- (2-methylphenyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine-11 -propanamine, o) 6- (2-ethylphenyl) -H, H-dimethyl-11H-pyrido [2,3-b] [1b] benzodiazepine-11-propanamine, p) 6- (2-methoxyphenyl) -N N-dimethyl-11H-pyrido [2,3-b] [1-benzodiazepine-11-propanamine, q.) 6- (2,1-dichlorophenyl) -H, 1-dimethyl-11 H-pyrido [2,3- b] [1, ¼benzodiazepine-11-propanamine, and 25 r) N, N-dimetliyl-6- (3b, 5-trimethoxyphenyl) -11 H-pyrido [2,3-b] [1 bibenzodiazepine-1-propanamine .

YoOr images XXXIVa - XXXIVO

The following pyrido-benzodiazepines are prepared by the procedure of Example X, but with equal amounts of the compounds prepared in Example XXXEI instead of 9-chloro-6-phenyl-11H-pyrido [2,3-b] [1-bibenzodiazepine. : a) 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1b benzodiazepine-Π-propanamine, b) 7-chloro-H, H-dimethyl-6-phenyl -11H-pyrido [2,3-b] [1 bibenzodiazepine-11-propanamine, c). 9-broc-H, H-dimethyl-6-phenyl-11 H-pyrido [2,3-b] [1 bibenzodiazepine-11-propanamine, 8200549 h2 d) 9-ίΊ ^ Γ-ΙΙ, K-dimethyl-6 phenyl-11 H-pyrido [2,3-b] [1,1-benzodiazepine-11-propanamine, e) N, N-dimethyl-6-phenyl-9- (trifluoromethyl) -11 H-pyrido [2, 3-b] [1, h] benzodiazepine-11-propanamine, 5 f) N, H, 9-trimethyl-6-phenyl-11H-pyrido [2,3-b] [1] benzodiazepine-11-propanamine, g ) N, N, 8-trimethyl-β-phenyl-11H-pyrido [2,3-b] [1,1-benzodiazepine-11-propanamine, h) NN, N, T-trimethyl-6-phenyl-11H-pyrido [ 2,3-b] [1-A] benzodiazepine-11-propanamine, i) 9-ethyl-NyU-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1 A benzodiazepine-11 -propanamine, j) 9-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1A] benzodiazepine-11-propanamine, 15k) 9-ethoxy-N, N- dimethyl-6-phenyl-11H-pyrido [2,3-b] [1A] benzodiazepine-11-propanamine, 1) N, N-dimethyl-9-nitro-6-phenyl-11H-pyrido [2,3-b ] [1Abenzodiazepine-11-propanamine, m) N, N-dimethyl-8-nitro-6-phenyl-11H-pyrido [2,3-b] [1 Abenzodiazepine-11-20 propanamine, η) N, N -10-trimethyl-6-phenyl-11H-pyrido [2,3-b] [1A benzodiazepine-11-propanamine, and o) 10-chloro-N, N-dimethyl-6-phenyl-11 H-pyrido [ 2,3-b] [1 Abenzodiazepine-11-propanamine.

Examples XXXVa - XXXVc

Using the same procedure as in Example I but with equal molar amounts of the following compounds in place of 3-amino-2-chloropyridine: k-amino-3-chloropyridine, 33-amino-U-chloropyridine, and 2- amino-3-chloropyridine, there are obtained: a) 6-phenyl-11H-pyrido [3, Ub] [1 A benzodiazepine, b) 10-phenyl-5H-pyrido] A, 3-b] [1 Abenzodiazepine, and ^ c) 10-phenyl-5H-pyrido [3,2-b] phenyl benzodiazepine.

8200549 ^ 3

Examples XXXVIa - XXXVIc

Using the same procedure as in Example III, the following compounds are: [2 - [(4-amino-3-pyridinyl) amino] phenylmethanone, [2- [(3-amino-1 + -pyridinyl) amino] phenylmethanone, and [2 - [(2-amino-3-pyridinyl) amino] phenylmethanone,. converted to: a) 6-phenyl-11H-pyrido [3,4-b] [1,4] benzodiazepine, b) 10-phenyl-5H-pyrido [4,3-b] [1, b] benzodiazepine, and C) 10-phenyl-5H-pyrido (3,2-b] [1,4] benzodiazepine.

Examples XXXVIIa - XXXVIIc

By the same method as in Example IX but with equal molar amounts of the following compounds instead of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine: ^ ^ β-phenyl-11H-pyrido [ 3,4-b] [1,4] benzodiazepine, 10-phenyl-5H-pyrido [b, 3-b] [1,4-benzodiazepine, and 10-phenyl-5H-pyrido [3 »2-b] [1 4] benzodiazepine, there is obtained: a) H, N-dimethyl-6-phenyl-11H-pyrido [3,4-b] [1,4] benzodiazepine-11-propane-20. Amine fumarate, b) H, H-dimethyl-10-phenyl-5H-pyrido [4,3-b] [1,4] benzodiazepine-5-propan-amine fumarate, and c) H, H-dimethyl-10 -phenyl-5H-pyrido [3,2-b] [1,4] benzodiazepine-5-propaneamine fumarate.

25

Example XXXVIII

5,6-Pihydro-6-phenyl-H-methyl-1TH-pyrido [2,3-b] ,41,41-benzodiazepine-11-propanamine

To a solution of 1.4 g (0.0035 mol) of H [3- [6-2q phenyl) -11 H-pyrido [2,3-b] [1,4] benzodiazepine-11-yl] propyl] carbamic acid ethyl ester (from Example XXIX) in tetrahydrofuran was added under nitrogen 0.4 g (0.0105 mol) of lithium aluminum hydride and a weak exothermic reaction occurred. The mixture was cooled to prevent overheating. The mixture was stirred at boiling temperature for 16 hours. Thin layer chromatography indicated that only partial conversion had occurred. Hog 0.4 g (0.0105 mol) of lithium aluminum hydride was added 82 0 0 5 '- *' * 4 kk and the mixture was refluxed overnight. Thin layer chromatography indicated that the product essentially consisted of the the title of the compound mentioned in this example.

Foreseen XXXIX

5 6- (2-Thienyl) -11H-pyrido [2.3-b1] 1-benzodiazepine

In the same manner as in Example XX, [2 - [(3-amino-2-pyridinyl) aminophenyl] (2-thienyl) methanone was heated with p-toluenesulfonic acid as a catalyst in an organic solvent, while water was separated in a water trap , and the above-mentioned compound was obtained.

Example XL · 6- (3-Thienyl) -11H-pyrido- (2,3-b] [1, Mbenzodiazepine

In the same manner as in Example XX, [2- (3-amino-2-pyridinyl) aminophenyl] (3-thienyl) methanone is heated with p-toluenesulfonic acid as a catalyst in an organic solvent while removing the water with the water scavenger and the desired compound was formed. Example XLI

6- (2-Pyridinyl) -11 H-pyrido [2.3-b] [1-benzodiazepine

In the same manner as in Example III, [2 - [(3-20 amino-2-pyridinyl) amino] phenyl] (2-pyridinyl) methanone was cycled to the above compound.

Example XLII

6- (3-Pyridinyl) -11H-pyrido ['2,3-b] [1,1] benzodiazepine

In the same manner as in Example III, [2 - [(3-25 amino-2-pyridinyl) amino phenyl] (3-pyridinyl) methanone was cycled to the above compound. .

Example XLIII

6- (U-Pyridinyl) -11H-pyrido [2,3-b] [1] benzodiazepine

In the same manner as in Example III, [2 - [(3-30 amino-2-pyridinyl) amino] phenyl] (U-pyridinyl) methanol was cycled to the above compound.

Example XLIV

N, N-Dimethyl-6- (2-thienyl) -11H-pyrido [2,3-b] [1, U] benzodiazenin-11-propanamine 35 In the same manner as in Example XXIII, 6- (2- thienyl) -11H-pyrido [2,3-b] [1,1U] benzodiazepine reacted with sodium hydride and then with 3-dimethylaminopropyl chloride to form the above compound.

Example XLV

g ..N-Dimethyl-6- (3-thienyl) -11H-pyridof 2,3-b3 [1,1] benzodiazepine-11-propanamine 5 In the same manner as in Example XXIII, 6- (3-thienyl) - 11H-pyrido [2,3-b] [1,1 *] benzodiazepine reacted with sodium hydride and then with 3-dimethylaminopropyl chloride to form the above compound.

Example XLVI

10 g.N-Dimethyl-6- (2-pyridinyl) -11H-pyrido [2,3-b1 [1,1] benzodiazeplne-11-propanamine

In the same manner as in Example XXIII, 6- (2-pyridinyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine was reacted with sodium hydride and then with 3-dimethylaminopropyl chloride to form the above compound.

Example XLVII

N, g-Pimethyl-6- (3-pyridinyl) -11H-pyrido [2,3-b1 [1, U] benzodiazepine-11-propanamine

In the same manner as in Example XXIII, 6- (3-20 pyridinyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine was reacted with sodium hydride and then with 3-dimethylaminopropyl chloride to form the above compound.

Example XLVIII

g, g-Pimethyl-6- (U-pyridinyl) -11H-pyrido [2,3-b1 [1, Mbenzodiazeplne-11-25 propanamine

In the same manner as in Example XXIII, 6- (U-pyridinyl) -11H-pyrido [2,3-b] [1-benzodiazepine was reacted with sodium hydride and then with 3-dimethylaminopropyl chloride.

Examples XLIXa - XLIXg 30 In the same manner as in Example VI, the following methanone compounds are prepared in preparation 15: [2 - [(3-amino-4-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, [2 - [( 3-amino-5-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, [2 - [(3-amino-6-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, 35 [2 - [(3-amino -5,6-dimethyl-2-pyridinyl) amino] phenyl] phenylmethanone, [2 - [(3-amino-6-methoxy-2-pyridinyl) amino] phenyl] phenylmethanone, [2- [(3-amino-2 -methyl-1] -pyridinyl) amino} phenyl] phenylmethanone, and [2- [(3-amino-5-methoxy-2-pyridinyl) amino] phenyl] phenylmethanone, 82 0 0 τ ί h € converted to the following pyridobenzodiazepines: a) 1-methyl-6-phenyl-11H-pyrido [2,3-b] [1] -benzodiazepine, b) 3-methyl-6-phenyl-11H-pyrido [2,3-b ] [1, U] benzodiazepine, c) 2-methyl-6-phenyl-11H-pyrido [2,3-b] [1-benzodiazepine, 5 d) 2,3-dime thy 1-6-phenyl-11 H- pyrido [2,3-b] [1-Jbenzodiazepine, e) 2-methoxy-6-phenyl-11H-pyrido [2,3-b] [1, ^] benzodiazepine, and g) 3-methoxy-6-phenyl -11 H-pyrido [2, 3-b] [1, Jbenzodiazepine.

Examples La - Lg 10 In the same manner as in Example XXIII, the pyridobenzodiazepines prepared in Example XLIX were reacted with sodium hydride and with 3-dimetKylaminopropyl chloride to form the following compounds: a) NjUjk-trimethyl-6-phenyl-11H-pyrido [ 2,3-b] [1,1-benzodiazepine-11-propanamine, b) N, 3-trimethyl-6-phenyl-11H-pyrido [2,3-bJ [1-benzodiazepine-11-pro. paanamine, c) N, N, 2-trimethyl-6-phenyl-11H-pyrido [2,3-bJ [1] benzodiazepine-11-propanamine,. D) N, H, 2,3-tetramethyl-6-phenyl-11H-pyrido [2,3-bJ [1-benzodiazepine-11-propanamine, e) 2-methoxy-N, H-dimethyl-6-phenyl-11H -pyrido [2,3-bJ [1,1¼benzodiazepine-11-propanamine, f) H, N, 1-trimethyl-10-phenyl-5H-pyrido [4,3-b] [1, k] benzodiazepine-5- propanamine, and g) 3-methoxy-H, H-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine.

Examples Lla-Lie

In the same manner as in Example XXII but with the following compounds instead of [2 - [(3-amino-2-pyridinyl) amino J phenyl J (U-fluorophenyl] methanone: [2 - [(3-amino-2- pyridinyl) aminophenyl] (2-fluorophenylmethanone, [2 - [(3-amino-2-pyridinyl) aminophenyl] (2-chlorophenylmethane), and "[2 - [(3-amino-2-pyridinyl) amino J phenyl] (2- Bromophenylmethanone, 35, there is obtained: a) 6- (2-fluorophenyl) -11H-pyrido [2,3-bJ [1] benzodiazepine,.

8200549 1 * Τ b) 6r (2-chlorophenyl) -11H-pyrido [2,3-b] [1,4-benzodiazepine, and c) 6- (2-bromophenyl) -11H-pyrido [2,3-b} [1,4Jbenzodiazepine.

Examples Lila - LIIc 5 In the same manner as in Example XXIII with the following pyrido [1,4-benzodiazepines instead of 6- (4-fluorophenyl) -11H-pyrido [2,3-bJ [-1,4Jbenzodiazepine: 6 - (2-fluorophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine. 6- (2-chlorophenyl) -11H-pyrido [2,3-b] [1,4-benzodiazepine, 6- (2-bromophenyl) -11H-pyrido [2,3-b] [1,4-benzodiazepine, one obtains : a) 6- (2-fluorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, m.p. 92 - 94 ° C; (isopropyl alcohol / isopropyl ether), b) 6- (2-chlorophenyl) -N, H-dimethyl-11H-pyrido [2.33 [1.4] benzodiazepine-11-15 propanamine, m.p. 104-105 ° C; (isopropyl ether) and c) 6- (2-bromophenyl) -ST, N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, m.p. 96-9 ° C; (isopropyl ether).

Examples Lilia and LXIIb

In the same manner as in Example IX but with the following compounds instead of 3-dimethylaminopropyl chloride: 3-dimethylamino-2-methylpropyl chloride, and 4-dimethylaminobutyl chloride, there is obtained: a) N, H, g-trimethyl- 6- phenyl-11H-pyrido [2,3-bJ [1,4-benzodiazepine-11-25 propanamine fumarate, and b) N, H-dimethyl-6-phenyl-11H-pyrido [2,3-b J [1 .4benzodiazepine-11-butaneamine fumarate. -

Examples LIVa and LIVb

When the following compounds are used instead of 4- (3-chloropropyl) morpholine hydrochloride: 1- (3-chloropropyl) pyrrolidine hydrochloride, and 1- (3-chloropropyl) -4-methylpiperazine hydrochloride, in the process of Example XI there is obtained: 35 6-phenyl-11- [3- (1-pyrrolidinyl) propyl] 11H-pyrido [2,3-b] [1,4Jbenzo-diazepine, and 8200549 "........ .

U8 β-phenyl-11- [3- (4-methyl-1-piperazinyl) propyl] -11H-pyrido [2,3-b] [1,4] -benzodiazepine.

Examples LVa - LVc

When the following-5 compounds are used instead of 6-phenyl-11H-pyrido [2,3-b] [1,4] ben-zodiazepine: 8-methyl-6-phenyl-11H- in the method according to example IX pyrido [3,4-b] [1] benzodiazepine, 6- (4-chlorophenyl) -11 H -pyrido [3,4-b] [1,4] benzodiazepine, and 3-methoxy-6-phenyl- 11H-pyrido [3,4 ~ b] [1, benzodiazepine, 10, there are obtained: a) II, II, 8-trimethyl-6-phenyl-11 E-pyrido [3,4-b] [1,4] benzodiazepine-11-propanamine, and b) 6- (4-chlorophenyl) -N, N-dimethyl-11 H -pyrido [3,4-b] [1,4] benzodiazepine-11-propanamine, and 15 c) 3-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [3,4-b] [1,4-benzodiazepine-11-propanamine. -Examples LVIa - LVId

When the following compounds are used in the process of Example XVII instead of 8-chloro-6-phenyl-11H-py-20. rido [2,3-b] [1,4] benzodiazepine: 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine, 8-chloro-6- (2-nitrophenyl) -11H- pyrido [2,3-b] [1,4] benzodiazepine, 8-chloro-6- (2-chlorophenyl) -11H-pyrido [2,3-b] [1,1U] benzodiazepine, and 8-chloro-6 - (2-Bromophenyl) -11H-pyrido [2,3-b] [1,4-benzodiazepine, 25 there are obtained: a) 11-methyl-6-phenyl-11H-pyrido [2,3-b] [1, U] benzodiazepine, b) 8-chloro-11-methyl-6- (2-nitrophenyl) -11H-pyrido [2,3-b] [1,4] benzodiaze-. pine, mp. 165-166 ° C, (ethyl alcohol), c) 8-chloro-6- (2-chlorophenyl) -11-methyl-11H-pyrido [2.3 ~ b] [1.4] benzodia-30 zepine, mp. 150-152 ° C, (isopropyl alcohol / isopropyl ether), and d) 6- (2-bromophenyl) -8-chloro-11-methyl-11 H -pyrido [2,3-b] [1 Benzodiazepine, m.p. Mp 121-123 ° C (isopropyl ether).

Example LVII

N-Methyl-H- [3- (11H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl) propyl] carbamic acid methyl ester

This compound is prepared by reacting 6-phenyl-8 2 0 0 5 4 9 '~' .....'...... * + 9 11H-pyrido [2,3-¾] [1, b] "benzodiazepine with (3-chloropropyl) methylcarbamic acid methyl ester.

Example LVIIX

9-Hydroxy-ff, fl-dimethyl-6-phenyl-11 H-pyrido [2., 3-b 1 [1 Λ1 benzodiazepine-11-5 propanamine

This compound is prepared by reacting 11- [3- (dimethylamino) propyl] -9-methoxy-6-phenyl-11H-pyrido [2,3-b] [1] benzodiazepine with HJ and glacial acetic acid.

Example LIX v 10 3-Hydroxy-H, N-dimethyl-6-phenyl-11-pyrido [2,3-b] f 1, U] benzodiazepine-11-propanamine

This compound is prepared by reacting 3-methoxy-N, H-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine with HJ and glacial acetic acid .

15

T A B E L B

20

R

Yoor- R Ar Y Σ n salt image 1 H CgH5- Η H 0 2 H CgH5 H 8-C1 0 25 3 H CgH5 H 9-C1 0 ^ H 2-Cl-CgH ^ - H 8-C1 1 5 H U -Cl-CgHj ^ Η H 0 -, .- 6 H k-CB3-C ^ ~ HE 0 * - 7 H it »0CH3-C6H ^ - Η H 0 30 8 - (CH2) 3-H (CH3} 2 CgH ^ - H 8-C1 0 oxalate 9 CgHj.- Η H 0 fumarate 10 CgH ^ - Η H 0 fumarate 11 - (CHp CgH, - Η H 0 fumarate morpholinyl 5 12 - (CH2) 3-N (C2H ^ ) 2 CgHc-- Η H 0 oxalate 35 13 - (CH2) 3-H (CH3) 2 CgH ^ - H 9-C1 0 fumarate 82 0 0 5 4 9 '' "...... '... ........ ~ 50 TABLE B (Continued)

Pre- R Ar IZ n salt image _ _ _ _ _ _ 1 if - (CHg) CgH ^ - Η H 0 fumarate piperidinyl 5 15 - (CH2) 3-K (CH3) 2 if-Cl-CgH ^ - Η H 0 fumarate 16 - (CH2-H (CH3) 2 C6H5 "H 8" C1 0 oxalate 17 -CH3 C6H5- H 8-C1 0 18 - (CH2) 3-N (CH3) 2 If-CH ^ CgH ^ - Η H 0 fumarate N 19 - (CH2) 3-N (CH3) 2 if-OCH ^ CgH ^ - Η H '0 fumarate 10 20 H 3-Cl-CgH ^ - Η H 0 -' 21 - (CH2) 3 -N (CH3) 2 3-Cl-CgH ^ - Η H 0 fumarate 22 H if-F-CgH ^ - Η H 0 23 - (CHj - N (CR,) 9 if-FC / 'Hi- Η H 0 HCl, 2 3 3 2 & k 1/2 H20 15 2k - (CHp) 3-l- CA- Η H 0 - phthalimidoyl 25 - (CHpL-NH C ^ H - Η H 0 2 HCl,

J? 2 HgO

26 - (CH2) 3-m2 CgH5- Η H 0 - 20 27 - (0Ho), -H = CH- C ^ - Η H 0 oc2h3 6 5 28 - (CH2) 3-KHCH3 CgH5- Η H 0 2 HC1 29 - (CHp) -NHC (O) - CrH, - Η H 0 - og2h ^ °? 25 30 - (CHp), - IT (CH3) p CrH - Η H 12 HCl, ^ 5 0.5 h2o 31 a) Η If-C ^ -CgH ^ - Η Ξ 0 - b) H HO 0 - c) H if-Br-CgH ^ - Η H 0 - 30 d) H if-F-CgH ^ - Η H 0 e] H If-OCgH ^ -CgH ^ - Η H 0 f) H 'if-NOg-CgH ^ - Η H 0 - g) H lf-CF3-CgH ^ - Η H 0 - h) H If-CH ^ CgH ^ - Η H 0 - 35 i) H 3-CgHj-CgH ^ - Η Η θά) Η 3 -00Η3-06Η ^ Η H 0 - k) Η 3-002Η5-06Η ^ - Η H 0 l) H 2-I02-CgH ^ - Η H 0 82 0 0 5 4 9 ~ ...... '. ..... ".........." ........

51 T A B E L · B (Continued)

Pre- R Ar YZ n salt “picture _ _ _ _ _ _ m) H · 3-CP3-C6Hl4- · Η H 0 η) H 2-CH ^ -CgH ^ - Η H 0 5 ο) H '2- C2E5-C6Ek- Η H 0 p) H 2-OCHg-CgH ^ Η H 0 q) H 2, ^ (C1) 2-C6H3- Η H 0-- r) H 3, U, 5- (OCH,) , - Η H 0 C6H2- 3 10 32 a) H CgH ^ - H 8-C1 0 la) H CgH5- H T-Cl 0 c) H CgH ^ - H 9-Br 0 d) H CgH5- Η 9- P 0 e) H CgH5- H 9-CF3 0 15 f) HC ^ H5- H 9-C H3 0 g) H ° 6E5 ~ H 8_CH3 0 h) H CgH5- H T-CH3 0 i) H · CgH5- H 9-C2H5 0 j) H CgH5- H 9 “OCH3 0 20 k) H CgH5- H 9-OC2H5 0 l) H CgH ^ - H 9-HOg 0 m) H CgH ^ - H 8-K02 0 η) H C6H5- H 10-CH3 0 - ο) H CgH5- H 10-C1 0 25 33 a) - (CH2) 3-li (CH3) 2 hC ^ -C ^ - Η H 0 b) - (CH2) 3 -N (CH3) 2. k-i-C3H7-C6Hh- Η H 0 - c) - (CH2) 3-N (CH3) 2 WBr-CgH-Η H 0 - '. ! . d) - (CH2) 3-N (CH3) 2 FP-CgH ^ - Η H 0 e) - (CH2) 3-H (CH3) 2 ^ -OCgHj.-CgHjj- Η H 0 30 f) - (CH2 ) 3-n (C33) 2 k-NO2-C6Hk- EH 0 "g) - (CH2) 3-ff (CH3) 2 it_CF3-CgHu-Η H 0 h) - (CH2) 3-N (CH3) 2 3-CH3-C6Hr Η H 0 i) - (CH2) 3-N (CH3) 2 3-C2H5-C6H ^ - Η H 0 - j) - (CH2) 3-N (CH3) 2 3-0CE3-CgHj + - Η H 0 35 k) - (CH2) 3-H (CH3) 2 3-0C2H5-C6H ^ - Η H 0 1) - (CH2) 3-N (CH3) 2 2-NOg-CgH ^ - Η H 0 82 0 0 5 4 9 ------------------------------------------ ---------- 52 TABLE · B (Continued)

Pre- R Ar YZ n salt image _ _ _ _ _ _ m) - (CH2) 3-N (CH3) 2, 3-0ί3-06Η ^ -_ Η H 0 n) - (CH2) 3-W (CH3) ) 2 2-CK3-C6Ek- Η H 0 5 o) - (CH2) 3-R (CH3) 2 2-C2H5-C6H1 | - Η H 0-- p) - (CH2) 3-li (CH3) 2 2-0CH3-C6H ^ - Η H 0 q) - (CH2) 3-R (CH3) 2 2, U- (C1) 2-C6H3- Η H 0 r) - (CH2) 3-N (CH3) 2 3Λ, 5- (00Η3) 3- Η H 0 C6H2 3b a) - (CH2) 3-R (CH3) 2 CgH5- H 8-C1 0 io b) - (ch2) 3-h (ch3) 2 c6h5- H 7-C1 0 c) - (CH2) 3-N (CH3) 2 C6H5- H 9-Br 0 d) - (CH2) 3-H (CH3) 2 C6H5- 'H 9-F 0 e) - ( CH2) 3-N (CH3) 2 C6H5-H 9-CF3 0 f) - (CH2) 3-U (CH3) 2 CgH5-H 9-CH3 0 15 g) - (CH2) 3-N (CH3) 2 C5H5- H 8-CH3 0 h) - (CH2.) 3-R (CH3) 2 C6H5-H 7-CH3 0 i) - (CH2) 3-rr {CH3) 2 CgH5-H 9-C2H5 0 «Π - (CH2) 3-R (CH3) 2 C6H5-H 9-OCH3 0 k) - (CH2) 3-R (CH3) 2 C6H5-H 9-OC2H5 0 20 1) - (CH2) 3-H (CH3) ) 2 CgH5- H 9-H02 0 m) - (CH2) 3-N (CH3) 2 CgH5-H 8-NO2 0 n) - (CH2) 3-II (CH3) 2 CgH5-H 10-CH3 0 o ) - (CH2) 3-I (CH3) 2 C6H5- H 10-C1 0 38 - {c H253EHCH3 C6H5- h 'H 1 25 39 H 2-thienyl Η H 0 1 * 0 H 3-thienyl Η H 0: in H 2-pyridinyl Η H 0 b2 H 3-pyridinyl Η H 0 b3 H k-pyridinyl Η H 0 30 W + - (CH2) 3-N (CH3) 2 2-thi enyl Η H 0 k5 - (CH2) 3-N (CH3) 2 3-thienyl Η H 0 b6 - (CH2) 3-IT (CH3) 2 2-pyridinyl Η H 0 U7 - (CH2) 3-N (CH3 ) 2 3-pyridinyl EH 0 U8 - (CH2) 3-E (CH3) 2 U-pyridinyl Η H 0 82 0 0 5 4 9 '7 ----------------- --------------------------....... 7: -----; - * * 53 TABLE B (Continued)

Pre- E Ar Y Z n salt image _ _ _ _ __ _

h9 a) H C8 H5-U-CH3 .HO

b) H C6H5-3-CH3 H0 5 c) H C6V2-CH3 H0

d) H C 8 H 5 -2,3 (CH 3) 2 H

e) H CgH5-2-0CH3 H 0 g) H C6H5-3-0CH3 H0

50 a) - (CH 2) 3 -H (CH 3) 2 C 8 H 5 -CH 3 HO

10 b) - (CH2) 3-H (CH3) 2 CgH5- 3-CH3 H 0 c) - (CH2) 3-N (CH3) 2 C6H5-2-CH3 HO - 'd) - ((^ 2) ^ (0 ^) 2 C6H5- 2,3- (CH3) 2 H 0 - e) - (CH2) 3-N (CH3) 2 CgH5- 2-0CH3 H 0 g) - (ch2) 3-n (ch3 ) 2 c6h5- 3-och3 H 0 15 51 a) H 2-F-CgH ^ - Η H 0 b) H 2-Cl-CgH ^ - Η H 0 c) H2-Br-CgH ^ - Η H 0 52 a) - (CH2) 3-N (CH3) 2 2-F-CgH ^ - Η H 0 b) - (CH2) 3-U (CH3) 2 2-Cl-CgH ^ - Η H 0 20 c ) - (CH2) 3-N (CH3) 2 2-Br-CgH ^ Η H 0 53 a) -CH0CH (CHjCH0- C * H-- H HO fumarate b (Bh3) 2 3 2 65 b) - (CHg ) j ^ -N (CH3) 2 CgH ^ - H HO fumarate 5 ^ a) - (CHg) -1-pyrroli-: CgH_- Η H 0 dinyl · 5 5

B) - (CHg) 3-U-methyl-CgH-HO

piper azin-l-yl .: 56 a) -CH3 CgH5- H ·· H 0 - b) -CH3 2-NOg-CgH ^ - H 8-C1 0 e) -CH3 2-Cl-CgH ^ - H 8 -C1 0 30 d) -CH3 2-Br-CgH ^ - H 1 8-C1 0 5T - (CH ^) g-lT (CH3) - CgH5- Η H 0 5S - (CH2) 3-H (CH3) 2 CgH5- H 9-OH 0 59 - (CH2) 3-H (CH3) 2 C6H5- 3-OH H 0 82 0 0 5 4 9 .............. ... ..................-.....-------------------------- - 35 5¼ TABEPB (Continued) * r (H) n 5 - R ......... ·

Pre- R Ar IZ n salt “imaged _ _ _ _ _ _ 35 a) H CgH5- Η H 0 3 6 a) Ξ CgH5- Η H 0 10 37 a) - (CH2) 3-H (CH3) 2 C 1 -H HO fumarate 55 a) - (CH 2) 3-H (CH 3) 2 C 6 H 5 -H 8-CH 3 0 b) - (CH 2) 3-N (CH 3) 2 C 8 H 5 - 3-OCH 3 H 0 c) - (ch2) 3-n (ch3) 2 c6h5- H HO- 15, iolH'5cSu

R

2Q 35 b) H C6H5- Η H 0 - 3 6 b) H CgH5- Η H 0 37 b) - (CH2) 3-H (CH3) 2 CgH5- H HO fumarate b9 f) H CgH5- '1-CH3 H 0 50 f) - (ch2) 3-n (ch3) 2 cgH5- i-ch3 H 0 25 '- Ar

Zv

R

30 35 c) H CgH5- Η H 0 3 6 e) H CgH5- Η H 0 37 c) - (CH2) 3-H (CH3) 2 CgHj-- H HO fumarate 35

82 0 0 5 4 9 ----------------------------------------- --- ------------------------------- J

55

Formulation and Administration

Effective amounts of the above-mentioned pharmacologically active compounds of formulas Ip or of formula 2 can be administered to humans for therapeutic purposes by conventional administration methods and in conventional administration forms. For example, orally in the form of solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable carriers or parenterally in the form of sterile solutions.

Examples of solid carriers for oral administration are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.

Examples of liquid carriers for oral administration are vegetable oils and water.

For intramuscular administration, the carrier or excipient may consist of a sterile, parenterally acceptable liquid, for example, water or a parenterally acceptable oil, for example, peanut oil, in ampoules.

Although already very small amounts of the active substances according to the invention are active when a light treatment is intended or in cases of administration to patients with a small body weight, the dose is usually 5 mg or above and preferably 10, 25 50 or 100 mg or even more, which are most preferably administered three or four times a day, depending, of course, on the need of the situation, the compound used and the desired result. 25-200 Mg appears to be an optimal dosage unit and a useful range appears to be between 10 and 500 mg per dosage unit.

The usual daily dose will usually be between 0.3 and 20 mg / kg / day and preferably 0.3-10 mg / kg / day for the more active compounds. The active substances according to the invention can be combined with other compatible pharmacological active substances.

It is only necessary that the active agent according to the invention be present in an effective amount, that is, such that a suitable result will be achieved that is appropriate to the dosage form used. Of course, different dosage units can be administered at the same time. The correct individual dose as well as the daily dose will of course be determined. according to usual medi ......... 82 0 0 5 4 9 - = ------------------------- - Λ \ 56 chemical principles and upon the recommendation of a physician.

The following formulations are representative of the pharmacologically active compounds of the invention.

Formulation 5 1. Capsules

Capsules containing 10 mg and containing 50 mg of the active substance per capsule are manufactured. The amount of lactose can be reduced with the larger amounts of the refrigerant.

Typical mixture for capsules 10 mg 50 mg 10 _ per capsule per capsule

Active substance as a salt 10 50

Lactose 259 219

Starch 126 126

Magnesium stearate k k 15 total 399 399

Other capsule formulations preferably contain a higher dose of active agent and may be, for example, as follows:

Ingredients 100 mg 250 mg 500 mg _____________________ per capsule per capsule per capsule 20 Active substance as salt 100 250 500

Lactose 21U 163 95

Starch 87 81 1 * 7

Magnesium stearate ji 6 8 total 399 500 650 25 In each of these cases the selected active substance, lactose, starch and magnesium stearate are mixed before the mixture is filled in capsules.

2. Tablets

A typical formulation for a tablet with 5.0 mg of the active substance per tablet follows below.

This formulation can also be used for other amounts of active ingredient per tablet by adjusting the weight of the calcium calcium phosphate.

...... ¢ 2 0 0 5 4 9 ..............................; 57 • per tablet, mg 1. Active substance 10.0 2. ITai s starch 15.0 3. Corn starch (pasta) 12.0 5 Lactose 35.0 5 «Dicalcium phosphate '132.0 6. Calcium stearate 2.0 total 202 , 0

Mix components 1, 2, 4 and 5 evenly. Extend 10 component 3 like a 10 # * s paste in water. Granulate the former mixture with the starch paste and pass the wet mass through a 2.0 mm sieve. Dry the wet granules and strain them through a 1.4l mm mesh sieve. Mix the dried granules with the calcium stearate and beat into tahlets.

15 3.1% Sterile Injection Solution • per cc

Active substance mg 20

Preservative, pant.

chlorohutanol, w / vol. percent 0.5 20 Water for injections q.s.

Prepare the solution, prepare it by filtration, fill the solution in ampoules, seal it and sterilize in an autoclave.

Various modifications and equivalents will be apparent to those skilled in the art and may be incorporated in the selected compounds. in the mixtures and in the methods of the invention without departing from the spirit and scope of the invention and the invention is therefore limited only by the scope of the following claims.

8200549

Claims (56)

1. A compound selected from the group of formula I of the formula sheet, where: R is selected from hydrogen atoms, lower alkyl groups, ττ 112 1 -alk -MR R, and -alk -M = C-0C5H ,. groups; 5 12 ^ 5. R and R are selected from vessel atoms, low alkyl groups, -C (0) 0- low alkyl groups or 1 2 R and R together with the adjacent nitrogen atom can form a heterocyclic group selected from a 1-phthalimido, 1-pyrrole. lidinyl, 5-morpholinyl, 1-piperazinyl and k-substituted pierazin-1-yl group; Ar. Is selected from a 2-, 3-, or -pyridinyl, 2- or 3-thienyl or phenyl groups, each phenyl group may be substituted by 1-3 balogen atoms, lower alkyl groups, lower alkoxy groups, trifluoromethyl groups or nitro groups , many groups can be the same or different; alk ^ is a straight or branched hydrocarbon chain containing 1 to 8 carbon atoms, Z is selected from hydrogen or halogen atoms, lower alkyl groups, lower alkoxy groups, bydroxy or nitro groups, Y is selected from hydrogen or 1 to 2 groups selected from lower alkyl groups lower alkoxy groups or hydroxy groups, which may be the same or different, n is equal to 0 or 1, t file, from n is equal to 0 the dotted line is a double bond, and acid addition salts of these compounds. A compound according to claim 1, characterized in that it is 6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine. 3. A compound according to claim 1, characterized in that the 8-chloro-6-phenyl-11E-pyrido [2,3-b] [1,1U] is benzodiazepine. k. A compound according to claim 1, characterized in that it is 9-chloro-6-phenyl-11H-pyrido [2,3-b] [1, U] benzodiazepine. A compound according to claim 1, characterized in that it is 6 - (chlorophenyl) -11H-pyrido [2,3-b] {1,1U] benzodiazepine. 8200549 59 ^ A compound according to claim 1, characterized in that the 6- (1M-methylphenyl) -11H-pyrido [2,3-b] [1, U] is benzodiazepine. Compound according to claim 1, characterized in that it is 6- (k-methoxyphenyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine. A compound according to claim 1, characterized in that the 8-chloro-N, 11-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1, It] is benzodiazepine-11-propanamine. Compound according to claim 1, characterized in that the 8-chloro-U, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1, If-] benzodiazepine-10 11-propanamine oxalate [1: 1]. Compound according to claim 1, characterized in that it is H, N-dimethyl-6-phenyl-11 H -pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine. 11. A compound according to claim 1, characterized in that the 2f, U-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine fumarate [1 : 1]. 12. A compound according to claim 1, characterized in that the H, -ί-dimethyl-6-phenyl-11 H -pyrido [2,3-b] [1,1] benzodiazepine-11-ethane-amine is. Compound according to claim 1, characterized in that the H, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-ephan-amine fumarate [1: 1 ]. 1 ^. A compound according to claim 1, characterized in that it is 11 - [3- (U-morpholinyl) propyl] -β-phenyl-11 H -pyrido [2,3-b] [1] benzodia-25 zepine. Compound according to claim 1, characterized in that the 11- [3 - ((- - morpholinyl) propyl] -β-phenyl-11H-pyrido [2,3-b] [1,1]] benzodiazepine fumarate [1: 1]. - 16. A compound according to claim 1, characterized in that it is N, N-diethyl-6-phenyl-11H-pyrido [2,3-b] [1-benzodiazepine-11-propane-diamine. Compound according to claim 1, characterized in that it is H, ET-diethyl-6-phenyl-11H-pyrido [2,3-b] [1,1-benzodiazepine-11-propanamine oxalate [1: 1]. A compound according to claim 1, characterized in that it is 9-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1-benzodiazepine-11-propanamine. . . .82 0 05 4 9 - /: - * Compound according to claim 1, characterized in that the 9-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1 *] benzodiazepine-11-propanamine fumarate [ 1: 1]. 20. A compound according to claim 1, characterized in that 5 is 6-phenyl-11 - [3- (1-piperidinyl) propyl] 11H-pyrido [2,3-b] [1] benzodiazepine, A compound according to claim 1, characterized in that the 6-phenyl-11- [3- (1-piperidinyl) propyl] -11H-pyrido [2,3-b] [1,1U] benzo-diazepine fumarate [ 1: 1]. Compound according to claim 1, characterized in that the 6- (1; -chlorophenyl) -N, N-dimethyl 1-11H-pyrido [2,3-b] [1,1-benzodiazepine-11-propanamine is . Compound according to claim 1, characterized in that 6 - (- - chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,1-benzodiazepine-15-propanamine fumarate [1: 1]. 2k. A compound according to claim 1, characterized in that it is 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-ethanamine. · 25. A compound according to claim 1, characterized in that the 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-1-ethanamine oxalate [ 1: 1]. A compound according to claim 1, characterized in that it is 8-chloro-11-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4-benzodiazepine. 27. A compound according to claim 1, characterized in that it is 25N, H-dimethyl-6- (U-methylphenyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine. 28. A compound according to claim 1, characterized in that the. N, N-dimethyl-6- (U-methylphenyl) -11 H -pyrido [2,3-b] [1,1 +] benzodiazepine-11-propanamine fumarate [1: 1]. A compound according to claim 1, characterized in that it is 6- (b-methoxyphenyl) -IT, H-dimethyl-11H-pyrido [2,3-b] [1,1U] benzodiazepine-11-propanamine. 30. A compound according to claim 1, characterized in that the 6- (11-methoxyphenyl) -1, N-dimethyl-11H-pyrido [2,3-b] [1,1¼] benzodiazepine-11-propanamine fumarate. [1: 1]. ' A compound according to claim 1, characterized in that it ............. 82 0 0 5 4 9 - -.....-......... .......-............'...................— "* £ 6- (3-chlorophenyl 11 -H-pyrido [2,3-b] [1,1 +] is benzodiazepine. A compound according to claim 1, characterized in that it is 6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,1U] benzodiazepine-11-propanamine. A compound according to claim 1, characterized in that it is 6- (1-fluorophenyl) -11H-pyrido [2,3-bj [1,1] benzodiazepine. 3 ^. A compound according to claim 1, characterized in that it is 6 - (? - fluorophenyl) -H, H-dimethyl-11H-pyrido [2,3-b] [1,1]] benzodiazepine-11-propanamine. Compound according to claim 1, characterized in that the 11— [3 "(1» 3-dihydro-1,3-dioxo-2H-isoIndol-2-yl) propyl] -6-phenyl-11--pyrido [2,3-b] [1,1] benzodiazepine. A compound according to claim 1, characterized in that the 6-phenyl-11H-pyrido [2,3-b] [1, k] benzodi azepine-11-propanamine. A compound according to claim 1, characterized in that the 6-phenyl-11H-pyrido [2,3-b] [1,2] benzodiazepine-11-propanamine dihydrochloride is hemihydrate. 38. A compound according to claim 1, characterized in that the N- [3- [6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepin-11-yl] propyl] methanimide acid ethyl ester is. A compound according to claim 1, characterized in that the N-methyl-6-phenyl-11H-pyrido [2,3-b] [1, U] benzodiazepine-11-propanamine. ^ 0. A compound according to claim 1, characterized in that it is H-methyl-6-phenyl-11H-pyrido [2,3-b] [1,2] benzodiazepine-11-propanamine dihydrochloride. . ^ 1. A compound according to claim 1, characterized in that the H- [3- [6-phenyl-11H-pyrido [2,3-b3 [1,1] benzodiazepin-11-yl] propyl] carbamic acid is ethyl ester. 30 b2. A compound according to claim 1, characterized in that it is 5,6-dihydro-N, H-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,1U] benzodiazepine-11-propanamine. ij-3. A compound according to claim 1, characterized in that the 5,6-dihydro-H, H-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1] benzodiazepine-35 11-propanamine, dihydrochloride hemihydrate. U4. Compound according to claim 1, characterized in that it is ____________82 0 0 5 4 9 ..............._................. ......_____________________________________________ · 8-chloro-6- (2-phenyl) -5,6-dihydro-11H-pyrido [2,3-b] [1,1 +] is benzodiazepine. 1) 5. A compound according to claim 1, characterized in that the 5,6-dihydro-N-methyl-6-phenyl-11H-pyrido [2,3-b] [11] benzodiazepine-11-5 propanamine. 1) -6. A compound according to claim 1, characterized in that it is 6- (2-fluorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine. 1) Compound according to claim 1, characterized in that the 6- (2-chlorophenyl) -ΪΓ, Ν-dimethyl-11H-pyrido [2,3-b] [1,1+] benzodiazepine-11 - propanamine. 1 * 8. A compound according to claim 1, characterized in that it is 6- (2-bromophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,1) -] benzodiazepine-11-propanamine. 1) 9 · A compound according to claim 1, characterized in that the 8-chloro-11-methyl-6- (2-nitrophenyl) -11H-pyrido [2,3-b] [1,1 *] benzodia- zepine. 50. A compound according to claim 1, characterized in that the 8-chloro-6- (2-chloro-phenyl) -11-methyl-11H-pyrido [3,2-b] [1,1] benzodiazepine is. A compound according to claim 1, characterized in that it is 6- (2-bromophenyl} -8-chloro-11-methyl-11H-pyrido [2,3-b] [1] benzodiazepine. 52. A compound according to claim 1, characterized in that 6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,1] -] benzodiazepine-11- propanamine fumarate [1; 1 ']'. . A compound according to claim 1, characterized in that. the 6- (1 + -fluorophenyl) -N, N-dimethyl-1H-pyrida [2,3-h] [1,1U] benzodiazepine-11-propanamine hydrochloride hemihydrate. 30 5¾. A method of treating depressions, characterized in that an effective amount of a compound according to any one of claims 1 to 53 is administered to the patient. Pharmaceutical composition with anti-depressant activity containing an active compound with a pharmaceutically acceptable carrier therefor, characterized in that the active ingredient is a compound according to any one of claims 1 to 53. ...-. 82 0 0 5 4 9 ........................-............... -... .............. — .................. - 56 Compound of the general formula (2) of the formula sheet, characterized in that Ar is selected from 2-, 3- and V-pyridinyl, 2- or 3-thienyl or phenyl groups, while the phenyl group may be substituted 5 through 1-3 groups selected from balogen atoms lower alkyl groups, lower alkoxy groups, trifluoromethyl groups or nitro groups which groups may be the same or different; Z is selected from hydrogen or halogen atoms, lower alkyl groups, lower alkoxy groups, hydroxy groups or nitro groups; 10. is selected from hydrogen atoms or 1 to 2 groups selected from lower alkyl, hydroxy or lower alkoxy groups, which groups may be the same or different and their pharmaceutically acceptable acid addition salts. The compound of claim 56, which is [2 - [(3-amino-2-pyridinyl) amino] phenyl] phenylmethanone. 58. The compound of claim 56, which is [2 - [(3-amino-2-pyridinyl) amino] chlorophenyl] phenylmethanone. The compound of claim 56 which is [2 - [(3-amino-2-pyridinyl) amino] phenyl] (U-methylphenyl) methanone. The compound of claim 56, which is [2 - [(3-amino-2-pyridinyl) amino] -5-chlorophenyl] (2-chlorophenyl) methanone. The compound of claim 56, which is [2 - [(3-amino-2-pyridinyl) amino] -3-chlorophenyl] phenylmethanone. The compound of claim 56, which is [2 - [(3-ami-25-no-2-pyridinyl) amino] -1- fluorophenyl] phenylmethanone. The compound of claim 56, which is [2 - [(3-amino-, 2-pyridinyl) amino] phenyl] (3-chlorophenyl) methanone. 6k. A compound according to claim 56 which is [2 - [(3-amino-2-pyridinyl) amino] phenyl] (4-fluorophenyl) methanone. The compound of claim 56, which is [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-trifluoromethylphenyl) methanone. The compound of claim 56, which is [2 - [(3-amino-2-pyridinyl) amino] phenyl] -C 2 -fluorophenyl) methanone. The compound of claim 56, which is [2 - [(3-ami-35n} -2-pyridinyl] amino] phenyl] - (2-fluorophenyl) methanone. The compound of claim 56, which is [2 - [(3-amino- ...... 82.0 0 5 4 9. .................... ..._.............................................. 6 '2-Pyridinyl) amino] phenyl] - (2-chlorophenyl) methanone. The compound of claim 56, which is [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-bromophenyl) methanone. 70. A method of treating depressions, characterized in that a patient is administered to the patient a quantity of a compound as defined in claims 56-69. 71. A pharmaceutical composition having an anti-depressant effect comprising a additive as well as a pharmaceutically acceptable carrier therefor, characterized in that the preparation contains a additive as defined in claims 56-69. 72. Process for preparing compounds having the structure defined in claims 56-69, characterized in that a mixture of a halo-aminopyridine is used. of formula k and an (aminophenyl) aryl-methanoh of formula 3, wherein the substituents have the aforementioned significance, heated at 170-200 ° C for a shorter time than necessary for cyclization to the corresponding pyridobenzodiazepine, if desired wishes to separate the (2 - ((aminopyridinyl) amino) phenyl) arylmethanone formed and isolate with solvents to liberate it from starting materials and cyclized products. 73. Process for preparing pyrido (1.1if) benzodiazepines having the structure defined in claims 1-53, characterized in that a) a mixture of a compound of formula 3 and a compound of formula 1+ or a reaction product thereof of the formula II, wherein the substituents have the aforementioned meaning, as long as they are heated, such that water formed is removed and the starting material is cyclized to a pyrido (1.1 +) benzodiazepine of the formula 1a, and 'b) optionally reducing this compound with sodium boron cyanohydrin to form a compound of formula 1b-1. The process according to claim 73, characterized in that the mixture is heated to 170-200 ° C. 75. Process according to claim 73, characterized in that the water formed is removed under reflux in an aprotic solvent. 76. Process for preparing compounds having the structure defined in claims 1-53, characterized in that a) a mixture of a halo-aminopyridine of the formula and an (aminophenyl) arylmethanone of the formula 3, or a reaction product thereof of formula 2 heated such that the water formed is removed and the starting material is cyclized to a compound of formula 1a, wherein the various symbols have the aforementioned. meaning, b) if desired, reducing the compound obtained under a) with sodium boron cyanohydrin to form a compound of formula 1b-1, c) reacting the product obtained in step a) or b) with a haloalkalk Q reagent wherein Q is selected from the group consisting of -ff-Claagalkyl) -1,1-pyrrolidinyl, 1-pipericLinyl, U-substituted piperazin-1-yl, k-10 morpholino, 1-phthalimido, q -NC- 0- (lower alkyl) (lower alkyl) or halogen and, when n = 0, optionally reducing with sodium boron cyanohydrin, to form a compound of the general formula 1c, d) when Q is a phthalimido group, obtained in step c) react product with alcoholic hydrazine hydrate and an acid and, if n = 0, optionally reduce with sodium borohydrin to form a compound of formula 1e. e) optionally, reacting the product obtained in step d) with triethyl orthoformate for sufficient time to form a compound of formula 1e and then reducing this compound with sodium. borohydride to form a compound of formula 1e, f) if desired, react the product obtained in step d) with ethyl chloroformate (and triethylamine) followed by reduction with lithium aluminum hydride to form a compound of formula 1d, g) if desired a compound obtained at step c), wherein Q is an o: 30 -NC-O- (lower alkyl) (lower alkyl), to be hydrolyzed to a compound of formula 1b-3 and h) when Q is a chlorine atom, react a compound obtained in step c) with a dialkylamine under formation of a compound of formula 1b-3. 82 0 0 5 4 9 ..................................; ----